Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation

*Mubarak Muhammad*

## **Abstract**

Tumor necrosis factor (TNF) is one of the most extensively studied cytokine with about 19 distinct superfamily members and many more to be found. Prominent among these members is tumor necrosis factor alpha (TNF-α) that is known to be a potent promoter of inflammation, as well as many normal physiological functions in homeostasis and health and antimicrobial immunity. Nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) is one of the most important transcription factors that activate transcription of many proinflammatory genes, and the unraveling of TNF-α induced NFκB activation forms the foundation of TNF-α as major cytokine of neuroinflammation. This review discusses summary of literature on unique role of TNF-α in neuroinflammation and various agents that mediate neuroinflammation via TNF-α modulation.

**Keywords:** tumor necrosis factor, tumor necrosis factor alpha, neuroinflammation, cytokine, brain, inflammation

#### **1. Introduction**

Tumor necrosis factor (TNF) alpha is one of the first discovered cytokines shown by Carswell [1] in 1975 and was named for tumor regression activity induced in the serum of mice treated with *Serratia marcescens* polysaccharide [2]. Cytokines are low-molecular-weight peptides secreted by activated immune cells as well as stromal cells and exerting biological activities through binding to cognate receptors on cell surface. Cytokines are produced by a number of cell types, predominantly leukocytes that regulate a number of physiological and pathological functions including innate immunity, acquired immunity, and a plethora of inflammatory responses [3]. Cytokines excite or hinder the generation, propagation, and differentiation of different associated target cells positive on antigen induction, thus leading to mediation in the activity of diverse other cells involved in the immune response especially the more pronounced macrophages, mast cells, B cells, T cells, and natural killer (NK) cells. Thus, cytokine is regarded as secreted proteins with growth, differentiation, and activation functions that regulate and determine the nature of immune responses [4]. The broad classification of cytokines are termed in a group as follows: interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), colony stimulating factor (CSF), and chemokine and growth factor (GF), and these exerts biological functions through action mode and characteristics as paracrine,

autocrine, and endocrine. TNF being one of the prominent cytokine has about 19 different members of the TNF superfamily that includes tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TNF-β), TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), lymphotoxin-β (LT- β), CD40L, CD30L, 4-1BBL, CD27L, glucocorticoid-induced TND receptor ligand (GITRL), fibroblast-associated ligand (FasL), OX40 ligand (OX40L), LIGHT, A proliferation-inducing ligand (APRIL), B-cell-activating factor (BAFF), receptor activator of NFκB ligand (RANKL), vascular endothelial cellgrowth inhibitor (VEGI), and ectodysplasin A ((EDA)–A1, EDA-A2) [2].

disease state such as in the onset of focal cerebral ischemia or traumatic brain injury, however, the microglia response becomes inappropriately more reactive and exaggerated to produce plethora of inflammatory mediators that trigger apoptosis and exaggerate neuronal damage [12]. Therefore, microglia/macrophages are the key immune cells concerned with the protection of brain against injury. Their architectural and functional changes are linked with the liberation of injury signals induced by pathology. These cells are usually responsible for clearance of demised neural cells and allow for restoration of lost neuronal functions. However, when markedly activated by the damage-associated molecular patterns subsequent to a disease state, they can generate a huge amount of proinflammatory cytokines that are capable of interrupting neural cells and the blood-brain barrier, and manipulate

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

The primary function of microglia in the brain is to control any external aggression and neutralize its effect by a process of phagocytosis, which is a chronologically multistep system including oriented gradient motility (chemotaxis); identification

of alien foreign agents by membrane lectins and receptors (recognition);

encompassing flow round the injurious foreign agents into a vacuole/phagosome (engulfment); unraveling of intracellular secretor pools (granules); and liberation of innate antibiotics and enzymes into the phagosome, generation of reactive oxygen species by an intricate enzymatic system sequestrated on the phagocyte membrane and/or reactive nitrogen species by an inducible nitric oxide synthase, and decapitating and digestion of engulfed foreign substance in the multifaceted phagolysosomal medium (microbial killing) [13]. Therefore, there are four important events of phagocytosis: chemotaxis, recognition, engulfment, and microbial

Chemotaxis is the immediate restricted, valuable host inflammatory reaction that is initiated by local tenant macrophages, demised cells and tissues, plasma factors, and microbial products. Specifically, the closely generated factors of inflammation (cytokines, activated complement protein, kinins, etc.) and microbial factors construct chemotactic gradients, alter endothelial cell membrane receptors, and encourage decrease of the blood flow. Blood-borne monocytes/macrophages that are rolling along the endothelial surface act in response to the chemotactic and cell-mediated signals and are primarily activated to definitely attach to the endothelium by way of their membrane integrins; the second pace is transendothelial migration, denoted as diapedesis, followed by tilting motility toward the inflam-

Recognition involves identifying and attachment of particle to be ingested by the

Engulfment refers to microglia/phagocyte extension of cytoplasm (pseudopods)

flow around the injurious foreign agents or microbes after its binding with

microglia/phagocytes. There are two methods of recognition: opsonin/opsonin dependent/receptor mediated and non-opsonin/opsonin independent. Opsonin/ opsonin dependent is where microglia/phagocytes recognize pathogens via their membrane receptors for opsonins (e.g., complement factors C3b and iC3b and Fc component of immunoglobulins), which are present on the microbial surface, while non-opsonin/opsonin independent is where microglia/phagocytes recognize pathogens via microbial and phagocyte lectins [13]. Because microglia/phagocytes express high-affinity receptors for opsonin, the term opsonization is used to indicate a process, whereby injurious foreign particle becomes coated with substance, thereby enhancing its recognition by leukocyte and making it more open to phagocytosis. As aforementioned, the injurious foreign agents or microbes are usually opsonized by specific protein substances such as immunoglobulin G (IgG) antibodies, breakdown product of compliment (C3b), and fibrinogen all of which

neurogenesis [9].

killing.

**29**

matory site (chemotaxis) [13].

phagocytes express high-affinity receptors.

TNF-α is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health and antimicrobial immunity [5]. Inflammation is a classical host defense response of vascularized living tissue to infection and injury, and in the central nervous system (CNS), the term neuroinflammation is used to denote cellular and inflammatory responses of vascularized neuronal tissue through activation of resident cells in the brain (microglia, astrocytes, and endothelial cells), the recruitment of blood-derived leukocytes including neutrophils, lymphocytes, and macrophages, and a plethora of humoral factors [6, 7]. More appropriately, neuroinflammation is a term used to denote inflammation associated with the brain and is characterized by the activation of microglia and expression of major inflammatory mediators without typical features of peripheral inflammation such as edema and neutrophil infiltration [8]. Neuroinflammation in the brain supposedly has a positive effect such as increasing blood flow and removal of damaged tissue by phagocytosis, but in a disease state, the resulting inappropriate inflammation caused negative effects which by far out weight the positive effect [6].

Nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) otherwise called nuclear factor kappa B is a heterodimer and one of the most important transcription factors that activate transcription of many proinflammatory genes. It is well documented that TNF-α induces at least five different types of signals that include activation of NFκB, apoptosis pathways, extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38MAPK), and c-Jun N-terminal kinase (JNK) [2]. These biological functions of TNF-α makes its role in neuroinflammation critically prominent. It is therefore expedient to elucidate and expand the rational basis of TNF-α as major cytokine of neuroinflammation. Hence, this review discusses summary of literature on unique role of TNF-α in neuroinflammation and various agents that mediate neuroinflammation via TNF-α modulation.

#### **2. Neuroinflammation**

Microglia being major immune cells involved in defense in the central nervous system, its activation is considered to be the hallmark of neuroinflammation [7, 9]. Activation of microglia cells constitutes the first key acute response in the brain to external aggression such as acute brain ischemia, traumatic brain injury, or microbial pathogen, and this microglial activation is coupled with subsequent activation of blood-borne monocytes/macrophages to yield a full-blown neuroinflammatory thick rim around ischemia infarct that becomes observable after 1 week in both human and animal models [10]. Microglia in the CNS constitutes 5–15% of total brain population; having share common precursor with peripheral macrophages, they produced transient inflammatory changes like macrophages such as phagocytosis, inflammatory cytokine production, and antigen presentation, normally returning to their basal state when the activation stimulus is resolved [11]. In a

#### *Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

disease state such as in the onset of focal cerebral ischemia or traumatic brain injury, however, the microglia response becomes inappropriately more reactive and exaggerated to produce plethora of inflammatory mediators that trigger apoptosis and exaggerate neuronal damage [12]. Therefore, microglia/macrophages are the key immune cells concerned with the protection of brain against injury. Their architectural and functional changes are linked with the liberation of injury signals induced by pathology. These cells are usually responsible for clearance of demised neural cells and allow for restoration of lost neuronal functions. However, when markedly activated by the damage-associated molecular patterns subsequent to a disease state, they can generate a huge amount of proinflammatory cytokines that are capable of interrupting neural cells and the blood-brain barrier, and manipulate neurogenesis [9].

The primary function of microglia in the brain is to control any external aggression and neutralize its effect by a process of phagocytosis, which is a chronologically multistep system including oriented gradient motility (chemotaxis); identification of alien foreign agents by membrane lectins and receptors (recognition); encompassing flow round the injurious foreign agents into a vacuole/phagosome (engulfment); unraveling of intracellular secretor pools (granules); and liberation of innate antibiotics and enzymes into the phagosome, generation of reactive oxygen species by an intricate enzymatic system sequestrated on the phagocyte membrane and/or reactive nitrogen species by an inducible nitric oxide synthase, and decapitating and digestion of engulfed foreign substance in the multifaceted phagolysosomal medium (microbial killing) [13]. Therefore, there are four important events of phagocytosis: chemotaxis, recognition, engulfment, and microbial killing.

Chemotaxis is the immediate restricted, valuable host inflammatory reaction that is initiated by local tenant macrophages, demised cells and tissues, plasma factors, and microbial products. Specifically, the closely generated factors of inflammation (cytokines, activated complement protein, kinins, etc.) and microbial factors construct chemotactic gradients, alter endothelial cell membrane receptors, and encourage decrease of the blood flow. Blood-borne monocytes/macrophages that are rolling along the endothelial surface act in response to the chemotactic and cell-mediated signals and are primarily activated to definitely attach to the endothelium by way of their membrane integrins; the second pace is transendothelial migration, denoted as diapedesis, followed by tilting motility toward the inflammatory site (chemotaxis) [13].

Recognition involves identifying and attachment of particle to be ingested by the microglia/phagocytes. There are two methods of recognition: opsonin/opsonin dependent/receptor mediated and non-opsonin/opsonin independent. Opsonin/ opsonin dependent is where microglia/phagocytes recognize pathogens via their membrane receptors for opsonins (e.g., complement factors C3b and iC3b and Fc component of immunoglobulins), which are present on the microbial surface, while non-opsonin/opsonin independent is where microglia/phagocytes recognize pathogens via microbial and phagocyte lectins [13]. Because microglia/phagocytes express high-affinity receptors for opsonin, the term opsonization is used to indicate a process, whereby injurious foreign particle becomes coated with substance, thereby enhancing its recognition by leukocyte and making it more open to phagocytosis. As aforementioned, the injurious foreign agents or microbes are usually opsonized by specific protein substances such as immunoglobulin G (IgG) antibodies, breakdown product of compliment (C3b), and fibrinogen all of which phagocytes express high-affinity receptors.

Engulfment refers to microglia/phagocyte extension of cytoplasm (pseudopods) flow around the injurious foreign agents or microbes after its binding with

autocrine, and endocrine. TNF being one of the prominent cytokine has about 19 different members of the TNF superfamily that includes tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TNF-β), TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL),

lymphotoxin-β (LT- β), CD40L, CD30L, 4-1BBL, CD27L, glucocorticoid-induced TND receptor ligand (GITRL), fibroblast-associated ligand (FasL), OX40 ligand (OX40L), LIGHT, A proliferation-inducing ligand (APRIL), B-cell-activating factor (BAFF), receptor activator of NFκB ligand (RANKL), vascular endothelial cellgrowth inhibitor (VEGI), and ectodysplasin A ((EDA)–A1, EDA-A2) [2].

TNF-α is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health and antimicrobial immunity [5]. Inflammation is a classical host defense response of vascularized living tissue to infection and injury, and in the central nervous system (CNS), the term neuroinflammation is used to denote cellular and inflammatory responses of vascularized neuronal tissue through activation of resident cells in the brain (microglia, astrocytes, and endothelial cells), the recruitment of blood-derived leukocytes including neutrophils, lymphocytes, and macrophages, and a plethora of humoral factors [6, 7]. More appropriately, neuroinflammation is a term used to denote inflammation associated with the brain and is characterized by the activation of microglia and expression of major inflammatory mediators without typical features of peripheral inflammation such as edema and neutrophil infiltration [8]. Neuroinflammation in the brain supposedly has a positive effect such as increasing blood flow and removal of damaged tissue by phagocytosis, but in a disease state, the resulting inappropriate inflammation caused negative effects which by far out weight the

Nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) otherwise

called nuclear factor kappa B is a heterodimer and one of the most important transcription factors that activate transcription of many proinflammatory genes. It is well documented that TNF-α induces at least five different types of signals that include activation of NFκB, apoptosis pathways, extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38MAPK), and c-Jun N-terminal kinase (JNK) [2]. These biological functions of TNF-α makes its role in neuroinflammation critically prominent. It is therefore expedient to elucidate and expand the rational basis of TNF-α as major cytokine of neuroinflammation. Hence,

this review discusses summary of literature on unique role of TNF-α in

neuroinflammation and various agents that mediate neuroinflammation via TNF-α

Microglia being major immune cells involved in defense in the central nervous system, its activation is considered to be the hallmark of neuroinflammation [7, 9]. Activation of microglia cells constitutes the first key acute response in the brain to external aggression such as acute brain ischemia, traumatic brain injury, or microbial pathogen, and this microglial activation is coupled with subsequent activation of blood-borne monocytes/macrophages to yield a full-blown neuroinflammatory thick rim around ischemia infarct that becomes observable after 1 week in both human and animal models [10]. Microglia in the CNS constitutes 5–15% of total brain population; having share common precursor with peripheral macrophages, they produced transient inflammatory changes like macrophages such as phagocytosis, inflammatory cytokine production, and antigen presentation, normally returning to their basal state when the activation stimulus is resolved [11]. In a

positive effect [6].

*Cytokines*

modulation.

**28**

**2. Neuroinflammation**

phagocyte and subsequent pinches off to form vesicles (phagosome) that enclose the injurious foreign agents or microbes. Phagocyte extensions (pseudopods) finally engulf the injurious foreign agent or microbe in a vacuole and trigger the activation of two functions: the release of granule contents into the phagosome and the oxidative burst. Coiling engulfment is the most frequent unusual uptake: unilateral pseudopods wrap around the microorganism in multiple turns, giving rise to largely selfapposed pseudopodial surfaces [13].

active proteases such as elastase, cathepsin G, and proteinase 3. The synergistic interaction of oxygen-dependent and non-oxygen-dependent/oxygen-independent

Pathological consequences that result from a disease state of the brain, however, make microglia response becomes inappropriately exaggerated. Microglia when transformed into phagocytes can release a variety of substances many of which are

neurotrophic molecules such as brain-derived neurotrophic factor (BDNF), insulinlike growth factor I (IGF-I), several other growth factors, and anti-inflammatory factors, cytotoxic substances include proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 as well as other potential cytotoxic molecules including nitric oxide (NO), reactive oxygen species (ROS), and prostanoids. The uniquely outburst cytokines extensively studied in acute ischemic stroke are tumor necrosis factor-α (TNF-α); the interleukins (IL), IL-1β, IL-6, IL-20, and IL-10; and transforming growth factor (TGF)-β. Although IL-1β and TNF-α are proinflammatory that appears to exacerbate cerebral injury, TGF-β and IL-10 are anti-inflammatory that may exert neuroprotective effects, and IL-6 has both pro- and anti-inflammatory effects [16]. Astrocytes, like microglia, are also capable of secreting inflammatory factors such as cytokines, chemotaxis cytokines (chemokines), and NO in response

microbial killing systems generally results in pathogen killing [13].

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

to brain pathological state.

Puerarin Stroke model of rat middle cerebral artery occlusion

Stroke model of rat intraluminal middle

Stroke model of rat middle cerebral

Stroke model of rat middle cerebral

cerebral artery occlusion

artery occlusion

artery occlusion

Nicotine Stroke model of rat global cerebral ischemia

Glycyrrhizin (GRZ) Brain cognitive impairment and

Atorvastatin Stroke model of rat intracerebral hemorrhage

Angiotensin-(1–7) Stroke model of mice intracerebral hemorrhage

neuroinflammation of lipopolysaccharide treated Mice

TNF modulation.

Edaravone and scutellarin

metalloproteinase-8 inhibitor (M8I)

Wogonin (5,7 dihydroxy-8 methoxyflavone)

Matrix

**31**

cytotoxic and/or cytoprotective. While cytoprotective substances include

**3. Agents that mediate neuroinflammation via TNF-α modulation**

**Table 1** reveals researches of various agents that mediate neuroinflammation via

**Treatment Experimental model Related TNF finding References**

Modulate neuroinflammation by mark reduction in mRNA expression of tumor necrosis factor-α (TNF-α)

Modulate neuroinflammation by attenuating expression levels of

Modulate neuroinflammation by abrogating TNF-α expression

Modulate neuroinflammation by decrease in production of TNF-α

Modulate neuroinflammation by significant reduction of enhanced expression of tumor necrosis factor alpha (TNF-α)

Modulate neuroinflammation through inhibition of proinflammatory TNF-α

Modulate neuroinflammation by dose-dependent reduction of

Modulate neuroinflammation by decrease in levels of TNF-α

TNF-α

TNF-α

[17]

[18]

[19]

[20]

[21]

[8]

[22]

[23]

Microbial killing can be achieved through oxygen-dependent or oxygenindependent/non-oxygen-dependent method of pathogen or injurious agent killing. Oxygen dependent involves the use free radicals. A free radical is clearly referred to as atom or molecule having one or more unpaired electrons in valence shell or outer orbit and is competent for autonomous survival [14]. The strange quantities of odd electron(s) possess by a free radical make it unbalanced, short lived, and extremely reactive. This high reactivity makes free radical exert a pull on electrons from further compounds to reach steadiness. The newly pulled attacked molecule loses its electron and becomes a free radical itself, opening a chain of feedback cascade of reaction. Free radicals/oxidants derived from both endogenous sources and exogenous sources have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. They include reactive oxygen species (ROS) which are hydroxyl radicals (˙OH), superoxide (O2 ), hydrogen peroxide (H2O2), and reactive nitrogen species (RNS) which are nitric oxide (NO) and peroxynitrite (OONO). At reasonable or little concentrations, ROS/RNS encompasses desirable effects and engage in a variety of physiological purposes such as in immune function (i.e., guard in opposition to pathogenic microorganisms), in certain cellular signaling pathways, in mitogenic reaction, and in redox directive. Conversely, at excessively elevated concentrations, both ROS and RNS lead to oxidative stress and nitrosative stress, respectively, that potentially cause adverse effect to biological molecules [14].

The mechanism of oxygen-dependent microbial killing is initiated after engulfment where oxygen burst is activated to cause increase in oxygen consumption (50 to 100-fold increase) and metabolism; this leads to massive production of nicotinamide adenosine diphosphate (NADP) as by-product of adenosine triphosphate (ATP) generation by oxidative phosphorylation. The oxygen burst is unrelated to mitochondrial respiration and reflects the activity of the NADPH oxidase system in the cytosol and membrane constituents, which are separated in resting microglia/ phagocytes and are reassembled upon microglia/phagocytes activation. The generated NADP through NADPH oxidase enzyme activity generates superoxide (O2 ) which is further converted to hydrogen peroxide (H2O2) either spontaneously or through enzymatic catalysis of superoxide dismutase (SOD) enzyme by combining with hydrogen ion (H+ ). Both hydrogen peroxide (H2O2) and superoxide (O2 ) can cause microbial killing. For instance, H2O2 in the presence of myeloperoxidase (MPO) released from microglia/phagocytes azurophilic (primary) granules and a halide generates very potent oxidizing agents such as hypochlorous acid (HOCl) and chloramines [13]. Other oxidative species such as singlet oxygen has been suggested to be important for microbial killing through the formation of ozone [15].

Non-oxygen-dependent/oxygen-independent microbial killing is mediated by protein molecule and other factors that are mostly found within the lysosome such as lysozyme, lactoferrin, and elastase. Lysozyme is an enzyme that hydrolyzes Nacetyl glucosamine bond found in glycopeptide coat of all bacterial cell wall. Thus, non-oxygen-dependent/oxygen-independent microbial killing is dependent on protein and peptide antibiotics such as bactericidal permeability-increasing protein, cationic antimicrobial protein 37, and defensins that are stored in peroxidasepositive (azurophilic, primary) granules where they are together localize with

#### *Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

active proteases such as elastase, cathepsin G, and proteinase 3. The synergistic interaction of oxygen-dependent and non-oxygen-dependent/oxygen-independent microbial killing systems generally results in pathogen killing [13].

Pathological consequences that result from a disease state of the brain, however, make microglia response becomes inappropriately exaggerated. Microglia when transformed into phagocytes can release a variety of substances many of which are cytotoxic and/or cytoprotective. While cytoprotective substances include neurotrophic molecules such as brain-derived neurotrophic factor (BDNF), insulinlike growth factor I (IGF-I), several other growth factors, and anti-inflammatory factors, cytotoxic substances include proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 as well as other potential cytotoxic molecules including nitric oxide (NO), reactive oxygen species (ROS), and prostanoids. The uniquely outburst cytokines extensively studied in acute ischemic stroke are tumor necrosis factor-α (TNF-α); the interleukins (IL), IL-1β, IL-6, IL-20, and IL-10; and transforming growth factor (TGF)-β. Although IL-1β and TNF-α are proinflammatory that appears to exacerbate cerebral injury, TGF-β and IL-10 are anti-inflammatory that may exert neuroprotective effects, and IL-6 has both pro- and anti-inflammatory effects [16]. Astrocytes, like microglia, are also capable of secreting inflammatory factors such as cytokines, chemotaxis cytokines (chemokines), and NO in response to brain pathological state.

## **3. Agents that mediate neuroinflammation via TNF-α modulation**


**Table 1** reveals researches of various agents that mediate neuroinflammation via TNF modulation.

phagocyte and subsequent pinches off to form vesicles (phagosome) that enclose the injurious foreign agents or microbes. Phagocyte extensions (pseudopods) finally engulf the injurious foreign agent or microbe in a vacuole and trigger the activation of two functions: the release of granule contents into the phagosome and the oxidative burst. Coiling engulfment is the most frequent unusual uptake: unilateral pseudopods wrap around the microorganism in multiple turns, giving rise to largely self-

Microbial killing can be achieved through oxygen-dependent or oxygenindependent/non-oxygen-dependent method of pathogen or injurious agent killing. Oxygen dependent involves the use free radicals. A free radical is clearly referred to as atom or molecule having one or more unpaired electrons in valence shell or outer orbit and is competent for autonomous survival [14]. The strange quantities of odd electron(s) possess by a free radical make it unbalanced, short lived, and extremely reactive. This high reactivity makes free radical exert a pull on electrons from further compounds to reach steadiness. The newly pulled attacked molecule loses its electron and becomes a free radical itself, opening a chain of feedback cascade of reaction. Free radicals/oxidants derived from both endogenous sources and exogenous sources have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. They include reactive oxygen species (ROS) which are hydroxyl radicals

(RNS) which are nitric oxide (NO) and peroxynitrite (OONO). At reasonable or little concentrations, ROS/RNS encompasses desirable effects and engage in a variety of physiological purposes such as in immune function (i.e., guard in opposition to pathogenic microorganisms), in certain cellular signaling pathways, in mitogenic reaction, and in redox directive. Conversely, at excessively elevated concentrations, both ROS and RNS lead to oxidative stress and nitrosative stress, respectively, that

The mechanism of oxygen-dependent microbial killing is initiated after engulfment where oxygen burst is activated to cause increase in oxygen consumption (50 to 100-fold increase) and metabolism; this leads to massive production of nicotinamide adenosine diphosphate (NADP) as by-product of adenosine triphosphate (ATP) generation by oxidative phosphorylation. The oxygen burst is unrelated to mitochondrial respiration and reflects the activity of the NADPH oxidase system in the cytosol and membrane constituents, which are separated in resting microglia/ phagocytes and are reassembled upon microglia/phagocytes activation. The generated NADP through NADPH oxidase enzyme activity generates superoxide (O2

which is further converted to hydrogen peroxide (H2O2) either spontaneously or through enzymatic catalysis of superoxide dismutase (SOD) enzyme by combining

cause microbial killing. For instance, H2O2 in the presence of myeloperoxidase (MPO) released from microglia/phagocytes azurophilic (primary) granules and a halide generates very potent oxidizing agents such as hypochlorous acid (HOCl) and chloramines [13]. Other oxidative species such as singlet oxygen has been suggested to be important for microbial killing through the formation of ozone [15]. Non-oxygen-dependent/oxygen-independent microbial killing is mediated by protein molecule and other factors that are mostly found within the lysosome such as lysozyme, lactoferrin, and elastase. Lysozyme is an enzyme that hydrolyzes Nacetyl glucosamine bond found in glycopeptide coat of all bacterial cell wall. Thus, non-oxygen-dependent/oxygen-independent microbial killing is dependent on protein and peptide antibiotics such as bactericidal permeability-increasing protein, cationic antimicrobial protein 37, and defensins that are stored in peroxidasepositive (azurophilic, primary) granules where they are together localize with

). Both hydrogen peroxide (H2O2) and superoxide (O2

potentially cause adverse effect to biological molecules [14].

), hydrogen peroxide (H2O2), and reactive nitrogen species

)

) can

apposed pseudopodial surfaces [13].

*Cytokines*

(˙OH), superoxide (O2

with hydrogen ion (H+

**30**


**4. Agents that induce neuroinflammation**

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

deficient models.

(TGF-β) [39].

involvement [40].

**33**

**TNF-α signaling**

In a comprehensive review of agents that induce neuroinflammation, Nazeem [39] has classified models of neuroinflammation based on mechanism through which agents induce neuroinflammation into three as follows: **i**mmune challengebased models which include lipopolysaccharide (LPS)-induced neuroinflammation and polyriboinosinic-polyribocytidilic acid (PolyI:C)-induced neuroinflammation;

neurotoxin-induced models which consist of streptozotocin-induced

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

neuroinflammation, okadaic acid-induced neuroinflammation, and colchicineinduced neuroinflammation; genetically manipulated models that contain interleukin-1β (IL-1β) overexpression model, p25 transgenic model, anti-nerve growth factor (NGF) transgenic models, and transforming growth factor-β (TGF-β)-

The most commonly studied model of neuroinflammation is LPS-induced neuroinflammation which activates microglia in the brain [40]. LPS also termed endotoxin is a constituent of the external membrane of Gram-negative bacteria, and the mechanism of LPS-induced neuroinflammation is mediated through LPS binding with CD14 on microglia membranes. The LPS-CD14 complex then interacts with the Toll-like receptor-4 (TLR-4), which, in turn, activates microglia by initiating signal transduction cascades leading to rapid transcription and release of proinflammatory cytokines, chemokines, and the complement system proteins, as well as anti-inflammatory cytokines like IL-10 and transforming growth factor-β

Another popular emerging noninvasive, effective, and sterile method of induction neuroinflammation in animal model is MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of contrast agent microbubbles (MB). This MRI-guided pFUS+MB has advantage over all other methods of inducing neuroinflammation in a way that it induces neuroinflammation without systemic

**5. Mechanism leading to the production of TNF-α in the brain and**

Upon cleavage by TACE/ADAM17, the free TNF-α forms a bioactive homotrimer that lead to biological effect of TNF-α. The actions of TNF-α is achieved through two distinct cell surface receptors: TNFR1 and TNFR2. TNF-α generates the activation of TNF receptors (TNFR1 and TNFR2), and the resultant TNF-induced TNFR signaling pathways are complex and wide ranging in different cell types, and precise circumstances, thereby accounting for TNF-α pleiotropic nature of action [5]. For instance, with TNFR1 signaling pathway, binding of TNF-α to the cognate receptor leads to the recruitment of TNF-α adaptor protein termed as TNF receptor-associated death domain (TRADD), which then creates a platform

ADAMs: A disintegrins and metalloproteinases) [41].

Within the brain, TNF-α is produced and discharged in the brain predominantly by glial cells and neurons, with microglia and astrocytes being the major glial cells involved. Upon arrival of appropriate TNF-α production stimulus, TNF-α is formed as a 27-kDa (233 amino acids) precursor, which binds to cell membrane of producing cells. This precursor is cleaved by proteolysis to liberate a 17-kDa (157 amino acids) subunit by the action of TNF alpha-converting enzyme (TACE). TACE also known as ADAM17 is well-identified proteinase enzyme that mediates the process TNF-α production and is a member in the family of mammalian adamalysins (or

#### **Table 1**

*Various agents that mediate neuroinflammation via TNF modulation*

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

## **4. Agents that induce neuroinflammation**

**Treatment Experimental model Related TNF finding References**

Modulate neuroinflammation through decrease in expression of

Modulate neuroinflammation through inhibition of lipopolysaccharide-induced production of TNF-α

Modulate neuroinflammation by inhibiting expression of tumor necrosis factor alpha

Modulate neuroinflammation by inhibiting increase in TNF-α

reduction of enhanced expression of tumor necrosis factor alpha (TNF-α) induced by ischemia/

Modulate neuroinflammation by inhibiting lipopolysaccharidemediated production TNF-α

Modulate neuroinflammation through attenuating release of TNF-α in the serum

Modulate neuroinflammation by inhibiting TNF-α induced by lipopolysaccharide treatment in primary microglia in a dosedependent manner

Modulate neuroinflammation by decrease in tumor necrosis

Modulate neuroinflammation by decrease in TNF-α levels

Modulate neuroinflammation by suppressing generation of proinflammatory TNF-α

Modulate neuroinflammation by reversing ischemia reperfusion injury induced elevation of TNF-

Modulate neuroinflammation by reduction of TNF-α activity

Modulate neuroinflammation by decreasing the expression of proinflammatory mRNA levels of

Modulate neuroinflammation by inhibiting lipoteichoic acid (LTA) induced expression of TNF-α

Modulate neuroinflammation by reduction in the expression of the proinflammatory cytokines TNF-

reperfusion

factor-α

α.

TNF-α

α

[24]

[25]

[26]

[27]

[21]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

cerebral TNF-α level

Stroke model of rat permanent middle

Stroke model of mice transient middle

Stroke model of rat transient middle cerebral artery occlusion

Nicotine Stroke model of rat global ischemia Modulate neuroinflammation by

cerebral artery occlusion

cerebral artery occlusion

lipopolysaccharide-induced inflammation in activated microglia

Stroke model of rat middle cerebral artery occlusion in vivo and lipopolysaccharide-induced microglial

lipopolysaccharide (LPS)-stimulated murine BV2 microglial cells

Brain neuroinflammation of lipoteichoic acid (LTA)-stimulated rat primary

demyelination induced by cuprizone in Mice model of multiple sclerosis.

Angiotensin-(1–7) Stroke model of rat permanent middle cerebral artery occlusion

Propofol Brain neuroinflammation of

Zileuton Stroke model of rat permanent middle cerebral artery occlusion

activation in vitro

Telmisartan Stroke model of rat intracerebral hemorrhage

Setarud (IMOD™) Human patients with acute ischemic stroke

SCH58261 Stroke model of rat bilateral common carotid artery occlusion

Caffeine Stroke model of rat bilateral common carotid artery occlusion

Fluoxetine Stroke model of rat subarachnoid hemorrhage

astrocytes

*Various agents that mediate neuroinflammation via TNF modulation*

Sildenafil Brain neuroinflammation and

Caffeine Brain neuroinflammation of

Milk fat globule-EGF factor VIII (MFG-

Compound K (20-O-D-glucopyranosyl-20

protopanaxadiol)

Caffeic acid ester fraction (Caf)

Matrix

**Table 1**

**32**

metalloproteinases 8 (MMP-8) inhibitor

Kaempferol glycosides

E8)

*Cytokines*

(S)-

In a comprehensive review of agents that induce neuroinflammation, Nazeem [39] has classified models of neuroinflammation based on mechanism through which agents induce neuroinflammation into three as follows: **i**mmune challengebased models which include lipopolysaccharide (LPS)-induced neuroinflammation and polyriboinosinic-polyribocytidilic acid (PolyI:C)-induced neuroinflammation; neurotoxin-induced models which consist of streptozotocin-induced neuroinflammation, okadaic acid-induced neuroinflammation, and colchicineinduced neuroinflammation; genetically manipulated models that contain interleukin-1β (IL-1β) overexpression model, p25 transgenic model, anti-nerve growth factor (NGF) transgenic models, and transforming growth factor-β (TGF-β) deficient models.

The most commonly studied model of neuroinflammation is LPS-induced neuroinflammation which activates microglia in the brain [40]. LPS also termed endotoxin is a constituent of the external membrane of Gram-negative bacteria, and the mechanism of LPS-induced neuroinflammation is mediated through LPS binding with CD14 on microglia membranes. The LPS-CD14 complex then interacts with the Toll-like receptor-4 (TLR-4), which, in turn, activates microglia by initiating signal transduction cascades leading to rapid transcription and release of proinflammatory cytokines, chemokines, and the complement system proteins, as well as anti-inflammatory cytokines like IL-10 and transforming growth factor-β (TGF-β) [39].

Another popular emerging noninvasive, effective, and sterile method of induction neuroinflammation in animal model is MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of contrast agent microbubbles (MB). This MRI-guided pFUS+MB has advantage over all other methods of inducing neuroinflammation in a way that it induces neuroinflammation without systemic involvement [40].

## **5. Mechanism leading to the production of TNF-α in the brain and TNF-α signaling**

Within the brain, TNF-α is produced and discharged in the brain predominantly by glial cells and neurons, with microglia and astrocytes being the major glial cells involved. Upon arrival of appropriate TNF-α production stimulus, TNF-α is formed as a 27-kDa (233 amino acids) precursor, which binds to cell membrane of producing cells. This precursor is cleaved by proteolysis to liberate a 17-kDa (157 amino acids) subunit by the action of TNF alpha-converting enzyme (TACE). TACE also known as ADAM17 is well-identified proteinase enzyme that mediates the process TNF-α production and is a member in the family of mammalian adamalysins (or ADAMs: A disintegrins and metalloproteinases) [41].

Upon cleavage by TACE/ADAM17, the free TNF-α forms a bioactive homotrimer that lead to biological effect of TNF-α. The actions of TNF-α is achieved through two distinct cell surface receptors: TNFR1 and TNFR2. TNF-α generates the activation of TNF receptors (TNFR1 and TNFR2), and the resultant TNF-induced TNFR signaling pathways are complex and wide ranging in different cell types, and precise circumstances, thereby accounting for TNF-α pleiotropic nature of action [5]. For instance, with TNFR1 signaling pathway, binding of TNF-α to the cognate receptor leads to the recruitment of TNF-α adaptor protein termed as TNF receptor-associated death domain (TRADD), which then creates a platform

for binding of additional cytoplasmic adaptor proteins including TNF receptorassociated factor 2 (TRAF2), receptor-interacting protein (RIP), and FASassociated death domain (FADD). The TRAF2 and RIP are concerned in escalating the transcriptional gene regulation; TRAF2 triggers the activation of a mitogenactivated protein kinase (MAPK) pathway, thereby leading to the activation of c-Jun N-terminal kinase (JNK), thus increasing its transcriptional activity; the RIP is a protein kinase vital to the activation of the transcription factor NFκB by phosphorylation of IκB kinase (IKK). On the other hand, FADD pathway leads to activation of caspase-8, thereby leading to initiate a caspase cascade of apoptosis cellular demise [41]. Although TNF-α binds to both TNFR1 and TNFR2 receptors with high affinity, there are some species specificity in terms of the receptor subtype and TNF-α binding [42]. TNF-α-induced p38 MAPK pathway transcription activity has been also implicated to induce proinflammatory IL-6 synthesis [43].

brain pathological processes, such as cerebral ischemia, leads to degradation of these inhibitors upon their phosphorylation by the IκB kinase (IKK), which allows NFκB to migrate into the nucleus, where it binds with DNA, and activates transcription of many proinflammatory genes [49]. This includes increase in expression of the genes for proinflammatory cytokines, chemokines, enzymes that generate mediators of inflammation, and adhesion molecules [50]. Thus, TNF-α both activate and are activated by NFκB, creating a type positive regulatory loop that amplify and perpetuate local inflammation [50]. Hence, these pathways of TNF-α-induced NF-kB explain the ability of TNF-α to induce other inflammatory cytokines such as IL-6

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

Apart from IκB-NFκB pathway, another intracellular signaling pathway through which TNF-α induces other inflammatory cytokines is Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. This JAK-STAT pathway can be initiated when there is TNF-α signaling after binding to its cognate receptors and consequently stimulates STATs. The STATs subsequently become activated and translocate to the nucleus to transmit transcriptional genetic expression of many cytokines, thereby leading to their syn-

Therefore, TNF-α is a proinflammatory cytokine that plays a critical role under both homeostatic and pathophysiological status within the central nervous system. Under healthy status, TNF-α has regulatory functions on vital physiological processes such as synaptic plasticity, learning and memory, sleep, food and water intake, and astrocyte-mediated synaptic amplification [51]. Under pathological status, astrocytes and mainly microglia excessively release massive concentration of TNF-α, thereby leading important constituent of neuroinflammatory response that marks a characteristic of several neurological disorders. Neuroinflammation itself at the first initial stage is a protective response in the brain, but excessively inappropriate inflammatory responses are detrimental, and in fact, it diminish the neuronal regeneration thereby leading to neurodegenerative diseases and other neurological

Microglia is a pivotal brain endogenous protective mechanism against various injuries agents. If such an injury is tolerable, it triggers cellular responses that protect the brain and precondition the body against more severe stimuli. Beyond tolerable level, it triggers response that may potentially aggravate brain injury. TNF-α is released by microglia-induced NFκB activation, and activated NFκB in turn activates more TNF-α. The IκB-NFκB pathway together with other intracellular signaling pathway such as p38 MAPK pathway and JAK-STAT pathway that all orchestrate cascade of cytokine production makes TNF-α so-called master regulator of neuroinflammatory cytokine production. This phenomenon forms the basis of

TNF-α as major cytokine of brain neuroinflammation.

The author declares no conflict of interest.

and IL-8 and synergize with interferons [5].

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

thesis [43].

disorders [52, 53].

**7. Conclusion**

**Conflict of interest**

**35**

## **6. TNF-α and neuroinflammation**

Neuroinflammation involves activation of microglia and astrocytes as well as influx of hematogenous cells recruited by cytokines, adhesion molecules, and chemokines across the activated blood vessel wall [44]. Neuroinflammatory signaling involves a coordinated effort of different molecules and cells types and is largely coordinated by a ubiquitous transcription factor NFκB. This signal transduction pathway for the activation of the transcription factor NFκB leads to control the expression of numerous genes activated during inflammation (i.e., cytokines, chemokines, growth factors, immune receptors, cellular ligands, and adhesion molecules). Thus, NFκB regulates a number of genes (including those coding for key inflammatory cytokines, like IL-6, TNF-α, etc.) involved in inflammation, making it the most important transcription factor that plays a key role in the inflammatory response. The collective gene targets of NFκB include various adhesion molecules, cytokines and chemokines (involved in proinflammatory signaling and NFκB activation, e.g., IL-1β and TNF-α), metalloproteinases (e.g., MMP-9), immune receptors, acute phase proteins, cell surface receptors, and inflammatory enzymes [45]. Various stimuli, such as cytokines, viruses, and oxidants, result in the activation of the transcription factor NFκB by separating it from inhibitor of NFκB alpha (IκBα) bound protein in the cytoplasm, which becomes degraded and allows NFκB to move to the nucleus, where it binds to the DNA of the genes for numerous inflammatory mediators, resulting in their increased production and secretion [46].

It is pertinent to note that neuroinflammatory microglia-/macrophage-mediated phagocytosis is instrumental in neutralizing injurious foreign agent and conducting brain cleanup, the process which must occur to allow for tissue repair and functional recovery. This fast and efficient removal of apoptotic, dislocated, and damaged cells, before the discharge of injurious and proinflammatory cell contents occur, may help to reduce secondary damage. But inappropriate inflammatory responses generated by microglia/macrophages in a disease state may aggravate brain injury [45].

Proinflammatory TNF-α being one of the most key important early initiators of neuroinflammation interacts with two receptors R1 and R2, to mediate extrinsic apoptotic death signal via Fas-associated death domain (FADD) and inflammation via nuclear factor kappa-light-chain enhancer of activated B cells (NFĸB), respectively [5]. NFκB is a major regulatory transcription factor with a pivotal role in inducing genes involved in inflammation [47]. In its dormant state, NFκB resides in the cytosol where it is bound to its inhibitory proteins known as inhibitors of NFκB (IκB), most commonly inhibitor of NFκB alpha (IκBα), making it unable to translocate into the nucleus [48]. Inflammatory stimuli resulting from wide range of

#### *Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

brain pathological processes, such as cerebral ischemia, leads to degradation of these inhibitors upon their phosphorylation by the IκB kinase (IKK), which allows NFκB to migrate into the nucleus, where it binds with DNA, and activates transcription of many proinflammatory genes [49]. This includes increase in expression of the genes for proinflammatory cytokines, chemokines, enzymes that generate mediators of inflammation, and adhesion molecules [50]. Thus, TNF-α both activate and are activated by NFκB, creating a type positive regulatory loop that amplify and perpetuate local inflammation [50]. Hence, these pathways of TNF-α-induced NF-kB explain the ability of TNF-α to induce other inflammatory cytokines such as IL-6 and IL-8 and synergize with interferons [5].

Apart from IκB-NFκB pathway, another intracellular signaling pathway through which TNF-α induces other inflammatory cytokines is Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. This JAK-STAT pathway can be initiated when there is TNF-α signaling after binding to its cognate receptors and consequently stimulates STATs. The STATs subsequently become activated and translocate to the nucleus to transmit transcriptional genetic expression of many cytokines, thereby leading to their synthesis [43].

Therefore, TNF-α is a proinflammatory cytokine that plays a critical role under both homeostatic and pathophysiological status within the central nervous system. Under healthy status, TNF-α has regulatory functions on vital physiological processes such as synaptic plasticity, learning and memory, sleep, food and water intake, and astrocyte-mediated synaptic amplification [51]. Under pathological status, astrocytes and mainly microglia excessively release massive concentration of TNF-α, thereby leading important constituent of neuroinflammatory response that marks a characteristic of several neurological disorders. Neuroinflammation itself at the first initial stage is a protective response in the brain, but excessively inappropriate inflammatory responses are detrimental, and in fact, it diminish the neuronal regeneration thereby leading to neurodegenerative diseases and other neurological disorders [52, 53].

### **7. Conclusion**

for binding of additional cytoplasmic adaptor proteins including TNF receptorassociated factor 2 (TRAF2), receptor-interacting protein (RIP), and FAS-

**6. TNF-α and neuroinflammation**

*Cytokines*

**34**

associated death domain (FADD). The TRAF2 and RIP are concerned in escalating the transcriptional gene regulation; TRAF2 triggers the activation of a mitogenactivated protein kinase (MAPK) pathway, thereby leading to the activation of c-Jun N-terminal kinase (JNK), thus increasing its transcriptional activity; the RIP is a protein kinase vital to the activation of the transcription factor NFκB by phosphorylation of IκB kinase (IKK). On the other hand, FADD pathway leads to activation of caspase-8, thereby leading to initiate a caspase cascade of apoptosis cellular demise [41]. Although TNF-α binds to both TNFR1 and TNFR2 receptors with high affinity, there are some species specificity in terms of the receptor subtype and TNF-α binding [42]. TNF-α-induced p38 MAPK pathway transcription activity has been also implicated to induce proinflammatory IL-6 synthesis [43].

Neuroinflammation involves activation of microglia and astrocytes as well as influx of hematogenous cells recruited by cytokines, adhesion molecules, and chemokines across the activated blood vessel wall [44]. Neuroinflammatory signaling involves a coordinated effort of different molecules and cells types and is largely coordinated by a ubiquitous transcription factor NFκB. This signal transduction pathway for the activation of the transcription factor NFκB leads to control the expression of numerous genes activated during inflammation (i.e., cytokines, chemokines, growth factors, immune receptors, cellular ligands, and adhesion molecules). Thus, NFκB regulates a number of genes (including those coding for key inflammatory cytokines, like IL-6, TNF-α, etc.) involved in inflammation, making it the most important transcription factor that plays a key role in the inflammatory response. The collective gene targets of NFκB include various adhesion molecules, cytokines and chemokines (involved in proinflammatory signaling and NFκB activation, e.g., IL-1β and TNF-α), metalloproteinases (e.g., MMP-9), immune receptors, acute phase proteins, cell surface receptors, and inflammatory enzymes [45]. Various stimuli, such as cytokines, viruses, and oxidants, result in the activation of the transcription factor NFκB by separating it from inhibitor of NFκB alpha (IκBα) bound protein in the cytoplasm, which becomes degraded and allows NFκB to move to the nucleus, where it binds to the DNA of the genes for numerous inflammatory

mediators, resulting in their increased production and secretion [46].

microglia/macrophages in a disease state may aggravate brain injury [45].

It is pertinent to note that neuroinflammatory microglia-/macrophage-mediated phagocytosis is instrumental in neutralizing injurious foreign agent and conducting brain cleanup, the process which must occur to allow for tissue repair and functional recovery. This fast and efficient removal of apoptotic, dislocated, and damaged cells, before the discharge of injurious and proinflammatory cell contents occur, may help to reduce secondary damage. But inappropriate inflammatory responses generated by

Proinflammatory TNF-α being one of the most key important early initiators of neuroinflammation interacts with two receptors R1 and R2, to mediate extrinsic apoptotic death signal via Fas-associated death domain (FADD) and inflammation via nuclear factor kappa-light-chain enhancer of activated B cells (NFĸB), respectively [5]. NFκB is a major regulatory transcription factor with a pivotal role in inducing genes involved in inflammation [47]. In its dormant state, NFκB resides in the cytosol where it is bound to its inhibitory proteins known as inhibitors of NFκB (IκB), most commonly inhibitor of NFκB alpha (IκBα), making it unable to translocate into the nucleus [48]. Inflammatory stimuli resulting from wide range of

Microglia is a pivotal brain endogenous protective mechanism against various injuries agents. If such an injury is tolerable, it triggers cellular responses that protect the brain and precondition the body against more severe stimuli. Beyond tolerable level, it triggers response that may potentially aggravate brain injury. TNF-α is released by microglia-induced NFκB activation, and activated NFκB in turn activates more TNF-α. The IκB-NFκB pathway together with other intracellular signaling pathway such as p38 MAPK pathway and JAK-STAT pathway that all orchestrate cascade of cytokine production makes TNF-α so-called master regulator of neuroinflammatory cytokine production. This phenomenon forms the basis of TNF-α as major cytokine of brain neuroinflammation.

#### **Conflict of interest**

The author declares no conflict of interest.

*Cytokines*

## **Author details**

Mubarak Muhammad Department of Human Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Bayero University Kano, Nigeria

**References**

**72**(9):3666-3670

2012;**119**(3):651-665

[1] Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences of the United States of America. 1975;

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

alleviates neuroinflammation and memory deficit induced by systemic lipopolysaccharide treatment in mice. Molecules. 2013;**18**:15788-15803

[9] Xiong XY, Liang L, Yang QW. Functions and mechanisms of microglia/macrophages in

2016;**5**(1):1-108

**2014**:1-9

615-650

neuroinflammation and neurogenesis during stroke. Progress in Neurobiology.

[10] Walberer M, Jantzen SU, Backes H, Rueder MA, Keuters MH, Neumaier B, et al. In-vivo detection of inflammation and neurodegeneration in the chronic phase after permanent embolic stroke in rats. Brain Research. 2014;**1581**:180-188

[11] Lee Y, Lee SR, Choi SS, Yeo HG, Chang KT, Lee HJ. Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke. BioMed Research International. 2014;

[12] Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: A double edged sword in ischemia/ reperfusion vs preconditioning. Redox

Biology. 2014;**2**:702-714

[13] Labro ME. Interference of antibacterial agents with phagocyte functions: Immunomodulation or "immuno-fairy tales"? Clinical Microbiology Reviews. 2000;**13**(4):

[14] Phaniendra A, Jestadi DB,

[15] Onyango AN. Endogenous

in human and animal tissues: Mechanisms, biological significance, and influence of dietary components. Oxidative Medicine and Cellular Longevity. 2016;**2016**:2398573

Periyasamy L. Free radicals: Properties, sources, targets, and their implication in various diseases. Indian Journal of Clinical Biochemistry. 2015;**30**(1):11-26

generation of singlet oxygen and ozone

[2] Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood.

[3] Sivangala R, Sumanlatha G. Cytokines that mediate and regulate immune responses. Innovative Immunology. 2015:1-26. https://www. austinpublishinggroup.com/ebooks/

Journal of Allergy and Clinical Immunology. 2010;**125**:54-72

cell death and inflammation to therapeutic giants—past, present and future. Cytokine and Growth Factor

Reviews. 2014;**25**:453-472

**24**:708-723

**37**

[4] Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: Cytokines, interferons, and chemokines.

[5] Sedger LM, McDermottc MF. TNF and TNF-receptors: From mediators of

[6] Denes A, Thornton P, Rothwell NJ, Allan SM. Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation. Brain, Behavior, and Immunity. 2010;

[7] Wang J, Yang Z, Liu C, Zhao Y, Chen Y. (2013). Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia. International Journal of Molecular Medicine. 2013;**31**(1):172-178

[8] Song JH, Lee JW, Shim B, Lee CY, Choi S, Kang C, et al. Glycyrrhizin

\*Address all correspondence to: mubarakmahmad@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

## **References**

[1] Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences of the United States of America. 1975; **72**(9):3666-3670

[2] Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;**119**(3):651-665

[3] Sivangala R, Sumanlatha G. Cytokines that mediate and regulate immune responses. Innovative Immunology. 2015:1-26. https://www. austinpublishinggroup.com/ebooks/

[4] Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: Cytokines, interferons, and chemokines. Journal of Allergy and Clinical Immunology. 2010;**125**:54-72

[5] Sedger LM, McDermottc MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine and Growth Factor Reviews. 2014;**25**:453-472

[6] Denes A, Thornton P, Rothwell NJ, Allan SM. Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation. Brain, Behavior, and Immunity. 2010; **24**:708-723

[7] Wang J, Yang Z, Liu C, Zhao Y, Chen Y. (2013). Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia. International Journal of Molecular Medicine. 2013;**31**(1):172-178

[8] Song JH, Lee JW, Shim B, Lee CY, Choi S, Kang C, et al. Glycyrrhizin

alleviates neuroinflammation and memory deficit induced by systemic lipopolysaccharide treatment in mice. Molecules. 2013;**18**:15788-15803

[9] Xiong XY, Liang L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis during stroke. Progress in Neurobiology. 2016;**5**(1):1-108

[10] Walberer M, Jantzen SU, Backes H, Rueder MA, Keuters MH, Neumaier B, et al. In-vivo detection of inflammation and neurodegeneration in the chronic phase after permanent embolic stroke in rats. Brain Research. 2014;**1581**:180-188

[11] Lee Y, Lee SR, Choi SS, Yeo HG, Chang KT, Lee HJ. Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke. BioMed Research International. 2014; **2014**:1-9

[12] Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: A double edged sword in ischemia/ reperfusion vs preconditioning. Redox Biology. 2014;**2**:702-714

[13] Labro ME. Interference of antibacterial agents with phagocyte functions: Immunomodulation or "immuno-fairy tales"? Clinical Microbiology Reviews. 2000;**13**(4): 615-650

[14] Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: Properties, sources, targets, and their implication in various diseases. Indian Journal of Clinical Biochemistry. 2015;**30**(1):11-26

[15] Onyango AN. Endogenous generation of singlet oxygen and ozone in human and animal tissues: Mechanisms, biological significance, and influence of dietary components. Oxidative Medicine and Cellular Longevity. 2016;**2016**:2398573

**Author details**

*Cytokines*

**36**

Mubarak Muhammad

Health Sciences, Bayero University Kano, Nigeria

provided the original work is properly cited.

\*Address all correspondence to: mubarakmahmad@yahoo.com

Department of Human Physiology, Faculty of Basic Medical Sciences, College of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[16] Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: Therapeutic approaches. Journal of Translational Medicine. 2009;**7**(97):1-11

[17] Chang Y, Hsie CY, Peng, ZA, Yen TL, Hsiao G, Chou DS, 3 Chen CM, Sheu JR: Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. Journal of Biomedical Science 2009; 16(9): 1–13.

[18] Yuan Y, Zha H, Ramgarajan P, Ling E, Wu C. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neuroscience. 2014;**15**: 125-133

[19] Han JU, Lee E, Moon E, Ryu JH, Choi JW, Kim H. Matrix metalloproteinase-8 is a novel pathogenetic factor in focal cerebral ischemia. Molecular Neurology. 2016; **53**(1):231-239

[20] Piao HZ, Jin SA, Chun HS, Lee J, Kim W. Neuro-protective effect of wogonin: Potential roles of inflammatory cytokines. Archives of Pharmacal Research. 2004;**27**(9): 930-936

[21] Guan Y, Jin X, Guan L, Yan H, Wang P, Gong Z, et al. Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Molecular Neurobiology. 2015;**51**(3): 1480-1488

[22] Ewen T, Qiuting L, Chaogang T, Tao T, Jun W, Liming T, et al. Neuroprotective effect of atorvastatin involves suppression of TNF-α and upregulation of IL-10 in a rat model of intra-cerebral haemorrhage. Cell Biochemistry and Biophysics. 2013;**66**(2):337-346

[23] Bihl JC, Zhang C, Zhao Y, Xiao X, Ma X, Chen Y, et al. Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory pathway. Vascular Pharmacology. 2015; **73**:115-123

brain damage following permanent cerebral ischemia in rats. Inflammation.

*DOI: http://dx.doi.org/10.5772/intechopen.85476*

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation*

exposed to cerebral ischaemia-

reperfusion injury. Nigerian Journal of Physiological Sciences. 2018;**33**:001-008

[36] Liu FY, Cai J, Wang C, Ruan W, Guan GP, Pan HZ, et al. Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: A possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway. Journal of

Neuroinflammation. 2018;**15**:347-459

[37] Lee EJ, Park JS, Lee YY, Kim DY, Kang JL, Kim HS. Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acidstimulated rat primary astrocytes: Involvement of NF-κB, Nrf2, and PPAR-γ signaling pathways. Journal of Neuroinflammation. 2018;**15**:326-338

[38] Nunes AKS, Raposo C, Rocha SWS, de Sousa Barbosa KP, de Almeidam RL, da Cruz-Höfling MA, et al. Involvement of AMP, IKβα-NFқB and eNOS in the sildenafil anti-inflammatory mechanism

[39] Nazem A, Sankowski R, Bacher M,

[40] Fung LK. A sterile animal model for

[41] Figiel I. Pro-inflammatory cytokine TNF-α as a neuroprotective agent in the

[42] Parameswaran N, Patial S. Tumor

[43] Tanabe K, Matsushuma-Nishiwaki R, Yamaguchi S, Iida H, Dohi S, Kozawa O.

in a demyelination model. Brain Research. 2015;**1**(62):119-133

Al-Abed Y. Rodent models of neuroinflammation for Alzheimer's disease. Journal of Neuroinflammation.

neuroinflammation? Science Translational Medicine. 2017;**9**:373

brain. Acta Neurobiologiae Experimentalis. 2008;**68**:526-534

necrosis factor-α signaling in macrophages. Critical Reviews in Eukaryotic Gene Expression. 2010;

2015;**12**:74

**20**(2):87-103

[30] Wang SX, Guo H, Hu LM, Liu YN, Wang YF, Kang LY, et al. Caffeic acid ester fraction from *Erigeron breviscapus* inhibits microglial activation and provides neuroprotection. Chinese Journal of Integrative Medicine. 2012;

[31] Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, et al. Blockade of AT1

inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. Journal of Pharmacology and Experimental Therapeutics. 2007;

[32] Farhoudi M, Najafi-Nesheli M, Hashemilar M, Mahmoodpoor A, Sharifipour E, Baradaran B, et al. Effect of IMOD™ on the inflammatory process

randomized clinical trial. DARU Journal of Pharmaceutical Sciences. 2013;

[33] Kanga C, Jayasooriyaa RG, Dilsharaa MG, Choib YH, Jeongc Y, Kimd ND,

lipopolysaccharide-stimulated BV2 microglial cells by suppressing Aktmediated NF-kB activation and ERK phosphorylation. Food and Chemical Toxicology. 2012;**50**:4270-4276

[34] Mohamed RA, Agha AM, Nassar NN. SCH58261 the selective adenosine A2A receptor blocker modulates ischemia reperfusion injury following bilateral carotid occlusion: Role of

Neurochemical Research. 2012;**37**:

[35] Muhammad M, El-ta'alu AB, Mabrouk MA, Yarube IU, Nuhu JM, Yusuf I, et al. Effect of caffeine on serum tumour necrosis factor alpha and lactate dehydrogenase in Wistar rats

after acute ischemic stroke: A

et al. Caffeine suppresses

inflammatory mediators.

538-547

**39**

receptor reduces apoptosis,

2010;**33**(5):344-352

**18**(6):437-444

**322**(3):1051-1058

**21**(26):1-8

[24] Cheyuo C, Jacob A, Wu R, Zhou M, Qi L, Dong W, et al. Recombinant human MFG-E8 attenuates cerebral ischemic injury: Its role in antiinflammation and anti-apoptosis. Neuropharmacology. 2012;**62**(2): 890-900

[25] Park JS, Shin JA, Jung JS, Hyun JW, Le TKV, Kim DH, et al. Antiinflammatory mechanism of compound K in activated microglia and its neuroprotective effect on experimental stroke in mice. Journal of Pharmacology and Experimental Therapeutics. 2012; **341**(1):59-67

[26] Yu L, Chu Chen C, Wang LF, Kuang X, Liu K, Zhang H, et al. Neuroprotective effect of Kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kB and STAT3 in transient focal stroke. PLoS One. 2013; **8**(2):1-11

[27] Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y. Suppressing inflammation by inhibiting the NF-kB pathway contributes to the neuroprotective effect of Angiotensin-(1-7) in rats with permanent cerebral ischaemia. British Journal of Pharmacology. 2012;**167**: 1520-1532

[28] Peng M, Ye JS, Wang Y, Chen C, Wang CY. Post treatment with Propofol attenuates lipopolysaccharide-induced up-regulation of inflammatory molecules in primary microglia. Inflammation Research. 2014;**63**(5): 411-418

[29] Tu K, Yang WZ, Wang CH, Shi SS, Chen CM, Yang YK, et al. Zileuton reduces inflammatory reaction and

*Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation DOI: http://dx.doi.org/10.5772/intechopen.85476*

brain damage following permanent cerebral ischemia in rats. Inflammation. 2010;**33**(5):344-352

[16] Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: Therapeutic approaches. Journal of Translational

counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory

**73**:115-123

890-900

**341**(1):59-67

**8**(2):1-11

1520-1532

411-418

pathway. Vascular Pharmacology. 2015;

[24] Cheyuo C, Jacob A, Wu R, Zhou M, Qi L, Dong W, et al. Recombinant human MFG-E8 attenuates cerebral ischemic injury: Its role in antiinflammation and anti-apoptosis. Neuropharmacology. 2012;**62**(2):

[25] Park JS, Shin JA, Jung JS, Hyun JW,

inflammatory mechanism of compound

neuroprotective effect on experimental stroke in mice. Journal of Pharmacology and Experimental Therapeutics. 2012;

[26] Yu L, Chu Chen C, Wang LF, Kuang

[27] Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y. Suppressing inflammation by

contributes to the neuroprotective effect

[28] Peng M, Ye JS, Wang Y, Chen C, Wang CY. Post treatment with Propofol attenuates lipopolysaccharide-induced

[29] Tu K, Yang WZ, Wang CH, Shi SS, Chen CM, Yang YK, et al. Zileuton reduces inflammatory reaction and

up-regulation of inflammatory molecules in primary microglia. Inflammation Research. 2014;**63**(5):

inhibiting the NF-kB pathway

of Angiotensin-(1-7) in rats with permanent cerebral ischaemia. British Journal of Pharmacology. 2012;**167**:

Neuroprotective effect of Kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kB and STAT3 in transient focal stroke. PLoS One. 2013;

Le TKV, Kim DH, et al. Anti-

K in activated microglia and its

X, Liu K, Zhang H, et al.

[17] Chang Y, Hsie CY, Peng, ZA, Yen TL, Hsiao G, Chou DS, 3 Chen CM, Sheu JR: Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. Journal of Biomedical Science

[18] Yuan Y, Zha H, Ramgarajan P, Ling E, Wu C. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neuroscience. 2014;**15**:

[19] Han JU, Lee E, Moon E, Ryu JH,

[20] Piao HZ, Jin SA, Chun HS, Lee J, Kim W. Neuro-protective effect of

inflammatory cytokines. Archives of Pharmacal Research. 2004;**27**(9):

[21] Guan Y, Jin X, Guan L, Yan H, Wang P, Gong Z, et al. Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Molecular Neurobiology. 2015;**51**(3):

[22] Ewen T, Qiuting L, Chaogang T, Tao T, Jun W, Liming T, et al. Neuroprotective effect of atorvastatin involves suppression of TNF-α and upregulation of IL-10 in a rat model of intra-cerebral haemorrhage. Cell Biochemistry and Biophysics. 2013;**66**(2):337-346

[23] Bihl JC, Zhang C, Zhao Y, Xiao X, Ma X, Chen Y, et al. Angiotensin-(1-7)

Choi JW, Kim H. Matrix metalloproteinase-8 is a novel pathogenetic factor in focal cerebral ischemia. Molecular Neurology. 2016;

wogonin: Potential roles of

Medicine. 2009;**7**(97):1-11

*Cytokines*

2009; 16(9): 1–13.

125-133

**53**(1):231-239

930-936

1480-1488

**38**

[30] Wang SX, Guo H, Hu LM, Liu YN, Wang YF, Kang LY, et al. Caffeic acid ester fraction from *Erigeron breviscapus* inhibits microglial activation and provides neuroprotection. Chinese Journal of Integrative Medicine. 2012; **18**(6):437-444

[31] Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, et al. Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. Journal of Pharmacology and Experimental Therapeutics. 2007; **322**(3):1051-1058

[32] Farhoudi M, Najafi-Nesheli M, Hashemilar M, Mahmoodpoor A, Sharifipour E, Baradaran B, et al. Effect of IMOD™ on the inflammatory process after acute ischemic stroke: A randomized clinical trial. DARU Journal of Pharmaceutical Sciences. 2013; **21**(26):1-8

[33] Kanga C, Jayasooriyaa RG, Dilsharaa MG, Choib YH, Jeongc Y, Kimd ND, et al. Caffeine suppresses lipopolysaccharide-stimulated BV2 microglial cells by suppressing Aktmediated NF-kB activation and ERK phosphorylation. Food and Chemical Toxicology. 2012;**50**:4270-4276

[34] Mohamed RA, Agha AM, Nassar NN. SCH58261 the selective adenosine A2A receptor blocker modulates ischemia reperfusion injury following bilateral carotid occlusion: Role of inflammatory mediators. Neurochemical Research. 2012;**37**: 538-547

[35] Muhammad M, El-ta'alu AB, Mabrouk MA, Yarube IU, Nuhu JM, Yusuf I, et al. Effect of caffeine on serum tumour necrosis factor alpha and lactate dehydrogenase in Wistar rats

exposed to cerebral ischaemiareperfusion injury. Nigerian Journal of Physiological Sciences. 2018;**33**:001-008

[36] Liu FY, Cai J, Wang C, Ruan W, Guan GP, Pan HZ, et al. Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: A possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway. Journal of Neuroinflammation. 2018;**15**:347-459

[37] Lee EJ, Park JS, Lee YY, Kim DY, Kang JL, Kim HS. Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acidstimulated rat primary astrocytes: Involvement of NF-κB, Nrf2, and PPAR-γ signaling pathways. Journal of Neuroinflammation. 2018;**15**:326-338

[38] Nunes AKS, Raposo C, Rocha SWS, de Sousa Barbosa KP, de Almeidam RL, da Cruz-Höfling MA, et al. Involvement of AMP, IKβα-NFқB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Research. 2015;**1**(62):119-133

[39] Nazem A, Sankowski R, Bacher M, Al-Abed Y. Rodent models of neuroinflammation for Alzheimer's disease. Journal of Neuroinflammation. 2015;**12**:74

[40] Fung LK. A sterile animal model for neuroinflammation? Science Translational Medicine. 2017;**9**:373

[41] Figiel I. Pro-inflammatory cytokine TNF-α as a neuroprotective agent in the brain. Acta Neurobiologiae Experimentalis. 2008;**68**:526-534

[42] Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Critical Reviews in Eukaryotic Gene Expression. 2010; **20**(2):87-103

[43] Tanabe K, Matsushuma-Nishiwaki R, Yamaguchi S, Iida H, Dohi S, Kozawa O.

Mechanisms of tumor necrosis factor-αinduced interleukin-6 synthesis in glioma cells. Journal of Neuroinflammation. 2010;**7**:16

[44] Moskowitz MA, Lo EH, Iadecola C. The science of stroke: Mechanisms in search of treatments. Neuron. 2010; **67**(2):181-198

[45] Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury. Stroke. 2011;**42**(6):1781-1786

[46] Barrett K, Brooks H, Boitano S, Barman S. Cellular and molecular basis of medical physiology. In: Ganong's Review of Medical Physiology. 23rd ed. USA: McGraw-Hill Publishers; 2010. pp. 51-61

[47] Bowie A, O'Neill LA. Oxidative stress and nuclear factor-kB activation: A reassessment of the evidence in the light of recent discoveries. Biochemical Pharmacology. 2000;**59**:13-23

[48] Berlo DV, Knaapen AD, Schooten RP, Albrech C. (2010). NF-κB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells. Particle and Fibre Toxicology. 2010;**7**(13):1-20

[49] Oeckinghaus A, Ghosh S. The NFkB family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology. 2009;**1**(4):1-14

[50] Barnes PJ, Karin M. Nuclear factorkB: A pivotal transcription factor in chronic inflammatory diseases. The New England Journal of Medicine. 1997; **336**(15):1066-1071

[51] Olmos G, Llado J. Tumour necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediators of Inflammation. 2014;**2014**: 861231

[52] Gresa-Arribas N, Vieitez C, Dentesano J, Saura J, Sola C. Modelling neuroinflammation in vitro: A tool to test the potential neuroprotective effect of anti-inflammatory agents. PLoS. 2012;**7**(9):e45227. DOI: 10.1371/journal. pone.0045227

[53] Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. Journal of Neurology Neurosurgery and Spine. 2016;**1**(1):1003

**41**

**Chapter 4**

**Abstract**

Treg subsets.

**1. Introduction**

*Xuehui He and Xinhui Wang*

TNFR2 and Regulatory T Cells:

Potential Immune Checkpoint

Target in Cancer Immunotherapy

TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human

**Keywords:** TNF, TNF receptor 2, regulatory T cells, immunotherapy,

CD4+FOXP3+ regulatory T cells (Treg) have an indispensable role in maintaining immune homeostasis and immune tolerance. They control unwanted immune responses that are involved in the regulation of immune tolerance to self as well as to foreign antigens. Loss-of-function mutation in *FOXP3* locus, a gene encoding Treg lineage transcription factor FOXP3, leads to multiorgan associated autoimmunity. Abnormal numbers of Treg and/or impaired suppressive function of Treg are often found in various autoimmune diseases like type 1 diabetes (T1D) [1], multiple sclerosis (MS) [2], rheumatoid arthritis (RA) [3], psoriasis [4–6], and systemic lupus erythematosus (SLE) [7–9]. On the other hand, tumor-infiltrating Treg generally show potent suppressive functions, indicating that they regulate tumorspecific immune responses and might help tumor immune escape [10]. It seems

autoimmune disease, cancer immunotherapy

## **Chapter 4**

Mechanisms of tumor necrosis factor-αinduced interleukin-6 synthesis in glioma cells. Journal of Neuroinflammation.

[52] Gresa-Arribas N, Vieitez C,

pone.0045227

2016;**1**(1):1003

Dentesano J, Saura J, Sola C. Modelling neuroinflammation in vitro: A tool to test the potential neuroprotective effect of anti-inflammatory agents. PLoS. 2012;**7**(9):e45227. DOI: 10.1371/journal.

[53] Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. Journal of Neurology Neurosurgery and Spine.

[44] Moskowitz MA, Lo EH, Iadecola C. The science of stroke: Mechanisms in search of treatments. Neuron. 2010;

[45] Aronowski J, Zhao X. Molecular

hemorrhage: Secondary brain injury.

[46] Barrett K, Brooks H, Boitano S, Barman S. Cellular and molecular basis of medical physiology. In: Ganong's Review of Medical Physiology. 23rd ed. USA: McGraw-Hill Publishers; 2010.

[47] Bowie A, O'Neill LA. Oxidative stress and nuclear factor-kB activation: A reassessment of the evidence in the light of recent discoveries. Biochemical

[48] Berlo DV, Knaapen AD, Schooten

[49] Oeckinghaus A, Ghosh S. The NFkB family of transcription factors and its

Perspectives in Biology. 2009;**1**(4):1-14

[50] Barnes PJ, Karin M. Nuclear factorkB: A pivotal transcription factor in chronic inflammatory diseases. The New England Journal of Medicine. 1997;

[51] Olmos G, Llado J. Tumour necrosis

neuroinflammation and excitotoxicity. Mediators of Inflammation. 2014;**2014**:

factor alpha: A link between

regulation. Cold Spring Harbor

**336**(15):1066-1071

861231

**40**

Pharmacology. 2000;**59**:13-23

RP, Albrech C. (2010). NF-κB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells. Particle and Fibre Toxicology. 2010;**7**(13):1-20

pathophysiology of cerebral

Stroke. 2011;**42**(6):1781-1786

2010;**7**:16

*Cytokines*

**67**(2):181-198

pp. 51-61
