**2. Cytokines**

The cytokine pattern that is released from the cell depends primarily on the nature of the antigenic stimulus and the type of cell being stimulated. Cytokines compromise leukocytes to respond to a microbial stimulus. Cytokines can be classified into six groups: (1) L1 superfamily, (2) TNF superfamily, (3) IL-17 family, (4) IL-6 superfamily, (5) type I superfamily, and (6) type II superfamily [5].

#### **2.1 IL-1 superfamily**

More than any other cytokine family, the interleukin (IL)-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll/interleukin-1 receptor (TIR) domain. This domain is also present in each Toll-like receptor (TLR), which responds to microbial products and viruses [6]. Since TIR domains are functional for both receptor families, responses to the IL-1 family are fundamental to the innate immunity [7].

#### *2.1.1 IL-1 family of cytokines and innate immune system*

There are 11 members of IL-1 family of cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra IL-37, and IL-38) and 10 members of the IL-1 family of receptors (IL-1R1 to ILR10) [8, 9]. More than any other cytokine family, the IL-1 family members are closely linked to damaging inflammation; however, the same members also work to increase nonspecific resistance to infection and the development of an immune response to a foreign antigen [10].

The numerous biological properties of the IL-1 family are nonspecific. The importance of IL-1 family members to the innate response became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type 1 (IL-1R1) is also found in the Toll protein of the fruit fly. The functional domain of the cytoplasmic component of IL-1R1 is termed the TIR domain. Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2 (COX-2), production of multiple cytokines and chemokines, increased the expression of adhesion molecules, or synthesis of nitric oxide (NO) are indistinguishable responses of both IL-1 and TLR ligands [11]. Both TLR and IL-1 families nonspecifically augment antigen recognition and activate lymphocyte function. The lymphocyte-activating function of IL-1 was first described in 1979 and is now considered a fundamental property of the acquired immune response. IL-1β is the most studied member of the IL-1 family due to its role in mediating auto-inflammatory diseases. Unquestionably, IL-1β evolved to assist host defense against infection, and this landmark study established how a low dose of recombinant IL-1β protects mice against lethal bacterial infection in the absence of neutrophils. Although we now accept the concept that cytokines like IL-1β served millions of years of evolution to protect the host, in the antibiotic and antiviral therapies era of today, we view cytokines as the cause of disease due to acute or chronic inflammation [12]. IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called auto-inflammatory diseases. The neutralization of IL-1β results in a rapid and

**11**

*2.2.1 TNF-α*

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

sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs, whereas neutralization of IL-1β is mostly anti-inflammatory. The auto-inflammatory diseases are caused due to gain-offunction mutations for caspase-1 activity, and common ailments, such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma, respond to the IL-1β neutralization [7]. IL-1 family also includes member that suppress inflammation, specifically within the IL-1 family, such as the IL-1 receptor antagonist (IL-1Ra), IL-36 receptor antagonist (IL-36Ra), and IL-37. In addition, the IL-1 family member IL-38, the last member of the IL-1 family of cytokines to be studied, nonspecifically suppresses inflammation and limits the

There are 10 members of the IL-1 family receptors. IL-1R1 binds IL-1α, IL-1β, and IL-1Ra and IL-R1 binds either IL-1β or IL-1α. IL-1R2 is a decoy receptor for IL-1β. IL-1R2 lacks a cytoplasmic domain and exists not only as an integral membrane protein but also in a soluble form. The term soluble is meant to denote the extracellular domain only. The soluble domain of IL-1R2 binds IL-1β in the extracellular space and neutralizes IL-1β. The neutralization of IL-1β by soluble IL-1R2 is greatly enhanced by forming a complex with IL-1R3. IL-1R3 is the co-receptor for IL-1α, IL-1β, IL-33, IL-36a, IL-36β, and IL-36γ. IL-1R3 exists as an integral membrane receptor or in a soluble receptor form. The inflammation and infection drive liver to increase the synthesis and levels of soluble IL-1R3 in the circulation [13].

Tumor necrosis factor superfamily (TNFSF) is a group of cytokines composed of 19 ligands and 29 receptors [14]. This family plays a pivotal role in immunity, inflammation and controlling cell cycle, proliferation, differentiation, and apoptosis [15]. TNFSF receptors can be divided into two different groups depending on the presence or absence of the intracellular death domain (DD) [16]. Signaling via the death domain demands the involvement of adapter proteins Fas-associated death domain (FADD) and TNF receptor-associated proteins (TRADD), leading to the activation of caspases that result in apoptotic death of a cell. The second group of TNFSF receptor signals acts only via adapter proteins termed tumor necrosis factor receptor-associated proteins (TRAFs). The DD containing receptors may use the pathway [17]. The functional activity of TNFSF receptors depends on the cellular context and the balance between pro- and antiapoptotic factors inside the cell and in the environment. Mostly, the TNFSF members are revealed on the cells of immune system and play a notable function in maintaining the equilibrium of T-cell–mediated immune responses by arranging direct signals required for the full activation of effector pool and survival of memory T cells. The TNFSF members are necessary in the development of pathogenesis of many T-cell–mediated autoim-

Tumor necrosis factor (TNF)-α is classified as homotrimeric transmembrane protein with a prominent role in systemic inflammation. Macrophages/monocytes are capable to produce TNF-α in the acute phase of inflammation, and this cytokine drives a wide range of signaling events within cells, leading to necrosis or apoptosis [17]. The TNF superfamily incorporates receptor activator of nuclear factor κB

mune diseases, such as asthma, diabetes, and arthritis [16].

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

innate immunity [12].

*2.1.2 IL-1 receptor family*

**2.2 TNF superfamily**

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

sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs, whereas neutralization of IL-1β is mostly anti-inflammatory. The auto-inflammatory diseases are caused due to gain-offunction mutations for caspase-1 activity, and common ailments, such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma, respond to the IL-1β neutralization [7]. IL-1 family also includes member that suppress inflammation, specifically within the IL-1 family, such as the IL-1 receptor antagonist (IL-1Ra), IL-36 receptor antagonist (IL-36Ra), and IL-37. In addition, the IL-1 family member IL-38, the last member of the IL-1 family of cytokines to be studied, nonspecifically suppresses inflammation and limits the innate immunity [12].

#### *2.1.2 IL-1 receptor family*

*Immune Response Activation and Immunomodulation*

pathogens [4].

**2. Cytokines**

**2.1 IL-1 superfamily**

mental to the innate immunity [7].

*2.1.1 IL-1 family of cytokines and innate immune system*

and survival, can also reprogram cells in the local tissue environment to improve certain types of immune responses. Therefore, cytokines are critical mediators of communication for the immune system and are essential for host defense against

The cytokine pattern that is released from the cell depends primarily on the nature of the antigenic stimulus and the type of cell being stimulated. Cytokines compromise leukocytes to respond to a microbial stimulus. Cytokines can be classified into six groups: (1) L1 superfamily, (2) TNF superfamily, (3) IL-17 family, (4)

More than any other cytokine family, the interleukin (IL)-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll/interleukin-1 receptor (TIR) domain. This domain is also present in each Toll-like receptor (TLR), which responds to microbial products and viruses [6]. Since TIR domains are functional for both receptor families, responses to the IL-1 family are funda-

There are 11 members of IL-1 family of cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra IL-37, and IL-38) and 10 members of the IL-1 family of receptors (IL-1R1 to ILR10) [8, 9]. More than any other cytokine family, the IL-1 family members are closely linked to damaging inflammation; however, the same members also work to increase nonspecific resistance to infection and the development of an immune response to a foreign antigen [10]. The numerous biological properties of the IL-1 family are nonspecific. The importance of IL-1 family members to the innate response became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type 1 (IL-1R1) is also found in the Toll protein of the fruit fly. The functional domain of the cytoplasmic component of IL-1R1 is termed the TIR domain. Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2 (COX-2), production of multiple cytokines and chemokines, increased the expression of adhesion molecules, or synthesis of nitric oxide (NO) are indistinguishable responses of both IL-1 and TLR ligands [11]. Both TLR and IL-1 families nonspecifically augment antigen recognition and activate lymphocyte function. The lymphocyte-activating function of IL-1 was first described in 1979 and is now considered a fundamental property of the acquired immune response. IL-1β is the most studied member of the IL-1 family due to its role in mediating auto-inflammatory diseases. Unquestionably, IL-1β evolved to assist host defense against infection, and this landmark study established how a low dose of recombinant IL-1β protects mice against lethal bacterial infection in the absence of neutrophils. Although we now accept the concept that cytokines like IL-1β served millions of years of evolution to protect the host, in the antibiotic and antiviral therapies era of today, we view cytokines as the cause of disease due to acute or chronic inflammation [12]. IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called auto-inflammatory diseases. The neutralization of IL-1β results in a rapid and

IL-6 superfamily, (5) type I superfamily, and (6) type II superfamily [5].

**10**

There are 10 members of the IL-1 family receptors. IL-1R1 binds IL-1α, IL-1β, and IL-1Ra and IL-R1 binds either IL-1β or IL-1α. IL-1R2 is a decoy receptor for IL-1β. IL-1R2 lacks a cytoplasmic domain and exists not only as an integral membrane protein but also in a soluble form. The term soluble is meant to denote the extracellular domain only. The soluble domain of IL-1R2 binds IL-1β in the extracellular space and neutralizes IL-1β. The neutralization of IL-1β by soluble IL-1R2 is greatly enhanced by forming a complex with IL-1R3. IL-1R3 is the co-receptor for IL-1α, IL-1β, IL-33, IL-36a, IL-36β, and IL-36γ. IL-1R3 exists as an integral membrane receptor or in a soluble receptor form. The inflammation and infection drive liver to increase the synthesis and levels of soluble IL-1R3 in the circulation [13].
