**5. Cytokine profile in viral infections**

In viral infections, the cytokines are implicated to establish an antiviral state as the unspecific first line of defense and virus-specific response. This process initiates through recognition of viral molecules by PRRs, which can be found as transmembrane receptors or in different intracellular compartment. The receptor undergoes a structural change, activating a route of signalization in the cytoplasm that end with the activation of cytoplasmic transcription factors that translocate into the nuclei to promote the expression of different cytokines. Depending of the virus and the type of cell, the type of cytokine produced may vary [70, 71].

#### **5.1 Pattern recognition receptors versus virus**

Viruses can infect virtually all cells of an organism. Epithelial, endothelial, fibroblasts, neurons, as well as innate and adaptive immune cells can be infected. PRRs are present in both nonhematopoietic origin cell and immune cells. Some PRRs recognize viral proteins, but other can detect viral single or double RNA or DNA. In human, there are 10 TLRs distributed in plasmatic membrane and endosome membranes. Of them, TLR-2 and TLR-4 can detect viral surface glycoprotein before the viral penetration. Others like TLR-3, TLR-8, and TLR-9 sense different types of viral nucleic acids in endosomes during virus entering. TLR-8 senses genomic ssRNA, TLR-3 senses dsRNA, and TLR-9 detects nonmethylated CpG viral DNA [72, 73]. Another type of receptors that sense viral RNA are the RNA helicases receptors like RIG-I and melanoma differentiation-associated gene 5 (MDA5) [71, 74]. These receptors have been demonstrated to detect viral dsRNA. This dsRNA can be genomic or an intermediate form during replication, which is formed, virtually, for all virus of single or double RNA during viral replication. However, there is evidence that some dsRNA replicative intermediators can translocate to endosomes where TLR can sense and trigger the signalization way [75].

#### **5.2 Cytokines produced in viral infections**

There are many cytokines with distinct functions. All of them are molecules with less than 20 KDa and can be pleiotropic or redundant, and also, they can synergize or antagonize each other. However, all of them are produced to ensure the virus elimination through the regulation of the immune response against the virus [76]. The process includes detection of the pathogen, signal to neighbor cells, activation and differentiation of innate immune cells, production of adhesion molecules on endothelial cell for extravasation of immune circulating cell, chemotactic molecules to attract cell to the infection foci, increase of phagocytosis, and

**19**

*and anti-inflammatory actions.*

**Figure 3.**

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens*

activation of adaptive cells to specifically eliminate infected cells and extracellular

Cytokine network against viruses starts with some cytokines produced by virus-infected cells (**Figure 3**). Epithelial cell can produce IFN, IL-8, IL-6, IL-1, GM-CSF [78, 79], TNFα [80], IL-18 [81], IL-12 [82], IL-2 [83], and IL-23 [84, 85]. The role of these cytokines is varied, IFN induces an antiviral state, and IL-8 is a potent inflammatory attracting phagocyte cell to the site of infection. IL-1 can promote apoptosis, and it is proinflammatory and chemotactic to neutrophils. GM-CSF is a hematopoietic grow factor that recruits various immune cells to host defense [76, 86]. Moreover, in the infection course, varies cytokines are also produced by innate and adaptive cell that can also be infected or activated. In filovirus infection, IL-1β, IL-5, IL-8, and IL-18, as well as varies chemokines like MIP-1α and β, monocyte chemoattractant protein 1 (MCP-1), and IFN-γ–inducible protein 10 (IP10) among others are produced [77]. In influenza virus infection, TNF-α, IL-1 α and β, and IL-6 and IL-8 are produced [87], and hepatitis C virus can promote the expression of IL-6, IL-8, MIP-1α, and MIP-1β and IL-1 [88], while rotavirus can induce the production of IFN, IL-8, IL-6, IL-1 [89], TNF-α [80], IL-18 [81], IL-12 [82], IL-2 [83], and IL-23 [84, 85]. Thus, the infected cell can upregulate multiple cytokine genes involved in different process as activation of NK, macrophages, and dendritic cells. Increasing the production of cytokines that serve as bridge between innate and adaptive response. In the inflammation process, virus-infected cells produce and secrete proinflammatory cytokines like IL-1, IL-6, IL-8, TNF [70] and

*Cytokines profile in viral infections. The immune response against viruses initiates through recognition of viral molecules by PRRs. These PRRs can activate a signal system culminating in the activation of transcription factors involved in the establishment of an antiviral state and an inflammation process. Cytokine network against viruses start with some cytokines produced by virus infected cells, such as IFNs, IL-8, IL-6, IL-1, GM-CSF, TNFα, IL-18, IL-12, IL-2 and IL-23, inducing a potent inflammatory response, attracting and activating phagocyte cells (e.g. neutrophils, macrophages, dendritic cells), mast cells and NK cells, to the site of infection. Furthermore, these cytokines are involved in the induction of an immune response type Th1/TCL with the purpose of eliminate infected cells and extracellular virus while cytokines such as IL-4, IL-10, IL-13, IL-37, and TGF-β modulate the immune response to a Th2 and Th17 phenotype, which produce immunomodulatory* 

*DOI: http://dx.doi.org/10.5772/intechopen.80843*

virus [77].

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens DOI: http://dx.doi.org/10.5772/intechopen.80843*

activation of adaptive cells to specifically eliminate infected cells and extracellular virus [77].

Cytokine network against viruses starts with some cytokines produced by virus-infected cells (**Figure 3**). Epithelial cell can produce IFN, IL-8, IL-6, IL-1, GM-CSF [78, 79], TNFα [80], IL-18 [81], IL-12 [82], IL-2 [83], and IL-23 [84, 85]. The role of these cytokines is varied, IFN induces an antiviral state, and IL-8 is a potent inflammatory attracting phagocyte cell to the site of infection. IL-1 can promote apoptosis, and it is proinflammatory and chemotactic to neutrophils. GM-CSF is a hematopoietic grow factor that recruits various immune cells to host defense [76, 86]. Moreover, in the infection course, varies cytokines are also produced by innate and adaptive cell that can also be infected or activated. In filovirus infection, IL-1β, IL-5, IL-8, and IL-18, as well as varies chemokines like MIP-1α and β, monocyte chemoattractant protein 1 (MCP-1), and IFN-γ–inducible protein 10 (IP10) among others are produced [77]. In influenza virus infection, TNF-α, IL-1 α and β, and IL-6 and IL-8 are produced [87], and hepatitis C virus can promote the expression of IL-6, IL-8, MIP-1α, and MIP-1β and IL-1 [88], while rotavirus can induce the production of IFN, IL-8, IL-6, IL-1 [89], TNF-α [80], IL-18 [81], IL-12 [82], IL-2 [83], and IL-23 [84, 85]. Thus, the infected cell can upregulate multiple cytokine genes involved in different process as activation of NK, macrophages, and dendritic cells. Increasing the production of cytokines that serve as bridge between innate and adaptive response. In the inflammation process, virus-infected cells produce and secrete proinflammatory cytokines like IL-1, IL-6, IL-8, TNF [70] and

#### **Figure 3.**

*Immune Response Activation and Immunomodulation*

**5. Cytokine profile in viral infections**

of cell, the type of cytokine produced may vary [70, 71].

**5.1 Pattern recognition receptors versus virus**

β-defensin 3 [66, 69].

of naïve CD4+ T cells into Th17 cells and the release of IL-17A, IL-17F and IL-22 in response to infections caused by mucosal fungi [68]. These cytokines in conjunction with IL-23 have various functions in the body from a proinflammatory, antiinflammatory, or regulatory activity, which depends on the type of microorganism, the site of infection, and the immunological status of the host (**Figure 2**). In vivo studies have shown that mice deficient of the IL-17 receptor (IL-17RA<sup>−</sup>/<sup>−</sup>) cannot limit systemic candidiasis, as well as oropharyngeal candidiasis, being more susceptible to developing mucocutaneous candidiasis, suggesting that the Th17 lineage strongly acts through IL-17, regulating the expansion, recruitment, and migration of neutrophils, as well as CXC-chemokines and antimicrobial proteins such as

In viral infections, the cytokines are implicated to establish an antiviral state as the unspecific first line of defense and virus-specific response. This process initiates through recognition of viral molecules by PRRs, which can be found as transmembrane receptors or in different intracellular compartment. The receptor undergoes a structural change, activating a route of signalization in the cytoplasm that end with the activation of cytoplasmic transcription factors that translocate into the nuclei to promote the expression of different cytokines. Depending of the virus and the type

Viruses can infect virtually all cells of an organism. Epithelial, endothelial, fibroblasts, neurons, as well as innate and adaptive immune cells can be infected. PRRs are present in both nonhematopoietic origin cell and immune cells. Some PRRs recognize viral proteins, but other can detect viral single or double RNA or DNA. In human, there are 10 TLRs distributed in plasmatic membrane and endosome membranes. Of them, TLR-2 and TLR-4 can detect viral surface glycoprotein before the viral penetration. Others like TLR-3, TLR-8, and TLR-9 sense different types of viral nucleic acids in endosomes during virus entering. TLR-8 senses genomic ssRNA, TLR-3 senses dsRNA, and TLR-9 detects nonmethylated CpG viral DNA [72, 73]. Another type of receptors that sense viral RNA are the RNA helicases receptors like RIG-I and melanoma differentiation-associated gene 5 (MDA5) [71, 74]. These receptors have been demonstrated to detect viral dsRNA. This dsRNA can be genomic or an intermediate form during replication, which is formed, virtually, for all virus of single or double RNA during viral replication. However, there is evidence that some dsRNA replicative intermediators can translocate to endosomes where TLR can sense and trigger the

There are many cytokines with distinct functions. All of them are molecules with less than 20 KDa and can be pleiotropic or redundant, and also, they can synergize or antagonize each other. However, all of them are produced to ensure the virus elimination through the regulation of the immune response against the virus [76]. The process includes detection of the pathogen, signal to neighbor cells, activation and differentiation of innate immune cells, production of adhesion molecules on endothelial cell for extravasation of immune circulating cell, chemotactic molecules to attract cell to the infection foci, increase of phagocytosis, and

**18**

signalization way [75].

**5.2 Cytokines produced in viral infections**

*Cytokines profile in viral infections. The immune response against viruses initiates through recognition of viral molecules by PRRs. These PRRs can activate a signal system culminating in the activation of transcription factors involved in the establishment of an antiviral state and an inflammation process. Cytokine network against viruses start with some cytokines produced by virus infected cells, such as IFNs, IL-8, IL-6, IL-1, GM-CSF, TNFα, IL-18, IL-12, IL-2 and IL-23, inducing a potent inflammatory response, attracting and activating phagocyte cells (e.g. neutrophils, macrophages, dendritic cells), mast cells and NK cells, to the site of infection. Furthermore, these cytokines are involved in the induction of an immune response type Th1/TCL with the purpose of eliminate infected cells and extracellular virus while cytokines such as IL-4, IL-10, IL-13, IL-37, and TGF-β modulate the immune response to a Th2 and Th17 phenotype, which produce immunomodulatory and anti-inflammatory actions.*

IFN. These cytokines can be involved in the early defense of the organism. They can activate cells present in the site of infection, and they can recruit leukocyte cells from circulating system through inflammation process (**Figure 3**).

### **5.3 Cytokines' role in viral infection**

IFN is a pleiotropic cytokine produced by virus infection. Although there are three types of IFN called type I (α/β), type II (γ) and type III (λ). Type I IFN plays an important role in control early viral infections. The role of type I IFN is to interfere with viral replication through activating the expression of antiviral molecules. Once IFN is secreted, it can act in autocrine or paracrine (like other cytokines) way, interacting with interferon receptor to induce the production of an antiviral state in the infected and noninfected neighboring cells, inhibiting different step of viral replication [76]. Also, IFN promotes the production of cytokines like IL-12, IL-6, IFN-γ, and TNF-α in innate cells including NK cells and macrophages [90]. Another function of IFN is to enhance differentiation of dendritic cells [91] and promote the antigen presentation [90] to stimulate T and B cells [92], which is redundant with the function of the IL-12 and IL-18 [93, 94]. NK cells are activated by synergism between type 1 IFNs and IL-12. However, cytokines such as IL-10, IL-6, IL-4, IL-13, and TGF-β suppress the actions of IFN, and these cytokines are known for their immunomodulatory and anti-inflammatory actions [95].

TNF-α is other pleiotropic cytokine produced by also nonhematopoietic infected cells and innate and adaptive immune cells, including macrophages, dendritic cells, natural killer, and T and B lymphocytes after being activated [96]. This cytokine can activate the production of adhesion molecules in endothelial cells and promote the extravasation of neutrophils, monocytes, and others immune cells to be attracted to infection foci. TNF also can participate in apoptosis through activating caspases. TNF-α, together with IFN-γ, acts on macrophages, inducing the production of superoxide anions and oxygen and nitrogen radicals [97]. Macrophages can also produce cytokines such as IL-1, IL-6, IL-23, IL-12, and more TNF-α [95].

IL-1 was the first interleukin to be identified and is a pleiotropic cytokine, and it acts synergically with IL-6 on the central nervous system, inducing fever by activation of the hypothalamus-pituitary-adrenal (HPA) axis [98]. This molecule also activates mast cells and induces histamine production, acting as a vasodilator, thus increases the permeability of the membrane [99]. Also, IL-1 is chemotactic factor that induces the passage of neutrophils to the site of infection. This chemotactic function is redundant with the action of IL-8, also known as chemokine CXCL8 [86] also produced by the infected cell. There are cytokines that antagonize these functions of IL-1 such as IL-10, IL-4, and IL-13 recognized for their anti-inflammatory actions [100].

Another pleiotropic cytokine is IL-18, first described as "interferon-γ-inducing factor" and member of IL-1 family. This interleukin and type I IFN are recognized by dendritic cells and trigger a signaling pathway through TRF6 and induce the expression of CD11b<sup>+</sup> in the surface of the cell [94]. These activated cells can express cytokines like IL-12, IL-6, IFN-γ, TNFα, and IFN-α, which also participates in other hematopoietic cells [101, 102]. IL-18 also participates synergistically with interleukin 12 on the activation of NK cells [93], stimulating the expression of CD25 and CD69 molecules, promoting their proliferation and cytotoxic capacity, respectively. Once activated, NK cells can induce apoptosis in virus-infected cells and produce other cytokines such as IL-12, IL-6, IL-10, IFN-γ, and TNF-α. Within the cytokines that block these functions of IL-18 are IL-37, IL-10, and TGF-β [103].

**21**

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens*

IL-6 is a soluble mediator with a pleiotropic effect on inflammation, immune response, and hematopoiesis. IL-6 is an important mediator of fever and of the acute phase response, which is redundant with IL-1 and TFN-α and promotes the differentiation of cytotoxic T lymphocytes, which induce the death of infected cells by osmotic lysis [104]. IL-6 synergistically with IL-23 participates in the differentiation of Th17 [105], through the production of RORγt. Once activated, Th17 induces inflammatory response through the expression of cytokines as IL-17 and IL-22. IL-6 also promotes the proliferation of B cells by binding to a complex of receptors (gp80, CD126, and CD130) [106] and, like IL-21 [107], induces the differentiation of plasma cells stimulating the antibody production [108]. However, there exist antagonist cytokines like IL-10, IL-13, and TGF-β that inhibit all these functions of

IL-12, also known as a T cell-stimulating factor, which together with IFN-γ, promotes differentiation of Th1 cells by activation of T-bet, and these cells can activate macrophages through expression of other cytokines like IFN and TNF, amplifying the produced immune response [109]. Although, there is evidence that viruses may selectively induce IFN production and Th1 differentiation even in the absence of

IL-2 participates in the differentiation and proliferation of Th2 (redundant with IL-4) and Treg cells by the expression of GATA-3 and FOXP3, respectively [111, 112]. Th2 cells can express IL-4, IL-5, IL-9, and IL-13, which also have pleiotropic effects in promoting type 2 effector mechanisms, such as B cells secretion of immunoglobulins, eosinophilia, mastocytosis, and M2 macrophage polarization [113]. Treg cells regulate the immune response, suppressing T-cell activation [114]. Treg and Th2 are known for their immunomodulatory and anti-inflammatory actions [95]. Finally, GM-CSF stimulates the generation of dendritic cells and participates in polarization of macrophages M1 [115]. Moreover, GM-CSF has also been associated with Th2 immunity and therefore M2 polarization. GM-CSF is considered a pleiotropic cytokine with inflammatory and anti-inflammatory functions [116].

In parasitic infections is difficult to generalize about the mechanisms of antiparasitic immunity because there is a great variety of different parasites that have different morphology and reside in different locations of tissues and hosts during their life cycles [117]. In this section of the chapter, we will talk about the immune response against protozoa and helminths, two of the main parasites of medical

Protozoan parasites are much larger and more complex pathogens than viruses or bacteria and have developed additional and sophisticated strategies to escape the immune attack of the host. Currently, 30% of humans suffer parasitic protozoan infections worldwide. Life cycles of protozoans generally involve several stages of specific antigenicity, which facilitates their survival and propagation within different cells, tissues, and hosts. Frequently, the host fails to eliminate protozoan infections, which often results in a chronic disease or inapparent infections, in which the

The immune defense mechanisms against protozoan parasites frequently involve several immune cells such as neutrophils, macrophages, and NK cells that mediate the innate response against extracellular protozoan parasites. NK cell and

**6.1 Immune system activation by parasitic protozoan infections**

host continues to act as a reservoir of parasites [118].

*DOI: http://dx.doi.org/10.5772/intechopen.80843*

**6. Cytokine profile in parasitic infections**

importance for human health.

the IL-6 [103].

IL-12 [110].

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens DOI: http://dx.doi.org/10.5772/intechopen.80843*

IL-6 is a soluble mediator with a pleiotropic effect on inflammation, immune response, and hematopoiesis. IL-6 is an important mediator of fever and of the acute phase response, which is redundant with IL-1 and TFN-α and promotes the differentiation of cytotoxic T lymphocytes, which induce the death of infected cells by osmotic lysis [104]. IL-6 synergistically with IL-23 participates in the differentiation of Th17 [105], through the production of RORγt. Once activated, Th17 induces inflammatory response through the expression of cytokines as IL-17 and IL-22. IL-6 also promotes the proliferation of B cells by binding to a complex of receptors (gp80, CD126, and CD130) [106] and, like IL-21 [107], induces the differentiation of plasma cells stimulating the antibody production [108]. However, there exist antagonist cytokines like IL-10, IL-13, and TGF-β that inhibit all these functions of the IL-6 [103].

IL-12, also known as a T cell-stimulating factor, which together with IFN-γ, promotes differentiation of Th1 cells by activation of T-bet, and these cells can activate macrophages through expression of other cytokines like IFN and TNF, amplifying the produced immune response [109]. Although, there is evidence that viruses may selectively induce IFN production and Th1 differentiation even in the absence of IL-12 [110].

IL-2 participates in the differentiation and proliferation of Th2 (redundant with IL-4) and Treg cells by the expression of GATA-3 and FOXP3, respectively [111, 112]. Th2 cells can express IL-4, IL-5, IL-9, and IL-13, which also have pleiotropic effects in promoting type 2 effector mechanisms, such as B cells secretion of immunoglobulins, eosinophilia, mastocytosis, and M2 macrophage polarization [113]. Treg cells regulate the immune response, suppressing T-cell activation [114]. Treg and Th2 are known for their immunomodulatory and anti-inflammatory actions [95]. Finally, GM-CSF stimulates the generation of dendritic cells and participates in polarization of macrophages M1 [115]. Moreover, GM-CSF has also been associated with Th2 immunity and therefore M2 polarization. GM-CSF is considered a pleiotropic cytokine with inflammatory and anti-inflammatory functions [116].
