**2.4 IL-6 superfamily**

IL-6 family is a group of cytokines and colony-stimulating factors (CSFs) that include IL-6, IL-27, IL-31, IL-35, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin (CT)-1, and cardiotrophin-like cytokine (CLC), among others [16, 17]. This cytokine family binds to its receptor, allowing a binding with the gp130 subunit [21, 22]. This binding allows dimerization of the subunit homogeneously or heterogeneously (either with the same subunit or cytokine receptor), creating a receptor complex. This complex allows associated proteins phosphorylation, such as Janus kinases (JAK) type 1, 2, and tyrosine kinase (TYK) 2, among others, which triggers a signaling pathway through phosphorylation toward types of signal transducer and activator of transcription (STAT) 1–6, forming another dimerization, homogeneous or

**13**

CD4+

and CD8+

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

heterogeneous with other STATs, that gets into the nucleus, recognizing promoter regions and initiating the regulation of the expression of specific genes [22, 23].

Type I cytokine family, also known as hematopoietins, is made up of several types of cytokines, including IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, IL-21, and granulocyte-macrophage colony-stimulating factor (GM-CSF), among others. This group of cytokines has α, β, and γ chain in common. IL-2, -4, -7, -9, -13, -15, and -21 have in common the γ chain (also known as IL2Rγ or CD132) for activation of JAK1/JAK3 and downstream STAT 1–5. While IL-3, -5, and GM-CSF share the common β chain (CSF2RB/CD131) for activation of the JAK/STAT pathway through interactions with JAK2 [3, 27], α chains do not activate signaling pathways but increase the binding affinity between the cytokine and β and γ subunit [3, 28], helping receptor specificity for gene expression [27]. While the receptor is more complex, there is more affinity of the cytokines of the receptor, which increases the signaling [27, 29]. The specificity of the receptor is conferred by α and β subunit, that in combination with γ subunit provides different stimulations. This means that the same cytokines can have different effects on the cell, depending on the receptor complexity; for example, IL-2 binds to its γ chain receptor (CD132) and β chain (IL-2Rβ), forming an intermediate affinity dimer, or also the binding of α chain (IL-2Rα), generating a high affinity. Phosphorylating tyrosine residues in JAKs, which lead to signaling to STAT5, prolonging and increasing its effect unlike the intermediate affinity [30]. Among the main functions of this cytokine family are the growth and differentiation of precursor leukocytes, as well as being modulators

The type II superfamily is composed of the subfamilies of interferons (IFNs) and IL-10. IFN family has the characteristic of inducing antiviral response in both hematopoietic and structural cells, serving as an essential mediator of cross talk between the immune system and host physiology during viral infections [3, 29].

Type I IFNs family is mainly composed of IFN-α and -β. IFN-α is expressed in leukocytes and IFN-β in fibroblasts, dendritic, and plasmacytoid cells. These IFNs have signaling pathways through JAK1 and TYK2 to phosphorylate STAT1 and STAT2 [29, 31]. These IFNs have a powerful proinflammatory effect and an antiviral response in immune and nonhematopoietic cells, as well as they can synergize with type II interferon (i.e., IFNγ) to potentiate Th1 lineage commitment by T-helper

 cells [3]. Type II IFNs family is composed only by IFN-γ, which is produced by active

T cells, NK cells, and macrophages by stimulation of IL-12, IL-18,

This family is divided into three types INFs families: types I, II, and III.

In IL-6 family, there are soluble receptors that have different signaling pathways, which are mostly of inhibitory function. Although they bind to the same cytokine and to the same subunit, they transmit different signaling called trans-signaling. It is observed that these soluble receptors prolong its effect and have action on cells where cytokine emerges effect; namely, all cells reactive to IL-6 will have the soluble receptor of IL-6 (IL-6Rs) function [21, 24]. Main functions of this IL-6 family cytokines are inflammation proteins production in acute phase, B cell differentiation into antibody-forming plasma cell, T cell modulator, development of Th17, and

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

hematopoiesis, among other functions [24–26].

and initiators of the inflammatory response [3, 27].

**2.5 Type I superfamily**

**2.6 Type II superfamily**

cells and cytotoxic activity by CD8<sup>+</sup>

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

heterogeneous with other STATs, that gets into the nucleus, recognizing promoter regions and initiating the regulation of the expression of specific genes [22, 23].

In IL-6 family, there are soluble receptors that have different signaling pathways, which are mostly of inhibitory function. Although they bind to the same cytokine and to the same subunit, they transmit different signaling called trans-signaling. It is observed that these soluble receptors prolong its effect and have action on cells where cytokine emerges effect; namely, all cells reactive to IL-6 will have the soluble receptor of IL-6 (IL-6Rs) function [21, 24]. Main functions of this IL-6 family cytokines are inflammation proteins production in acute phase, B cell differentiation into antibody-forming plasma cell, T cell modulator, development of Th17, and hematopoiesis, among other functions [24–26].

#### **2.5 Type I superfamily**

*Immune Response Activation and Immunomodulation*

*2.2.2 Biological roles of TNF-α*

**2.3 IL-17 family**

of immune homeostasis [19, 20].

**2.4 IL-6 superfamily**

(RANK), cluster of differentiation (CD)-40, CD27, and FAS receptor. This protein was discovered in the circulation of animals subsequent to the stimulation of their reticuloendothelial system and lipopolysaccharide (LPS) challenge. This protein has been found to provoke a rapid necrotic regression of certain forms of tumors [16].

Several biological functions are ascribed to the TNF-α, and for this reason, the mechanism of action is somewhat complex. Because this protein confers resistance to certain types of infections and in parallel causes pathological complications, it carries out contradictory roles. This may be connected to the varied signaling pathways that are activated. TNF-α modulates several therapeutic roles within the body, such as immunostimulation, resistance to infection agents, resistance to tumors, sleep regulation, and embryonic development [17]. On the other hand, parasitic, bacterial, and viral infections become more pathogenic or fatal due to TNF circulation. The major role of TNF is explicated as mediator in resistance against infections. Moreover, it was postulated that TNF plays a pathological role in several autoimmune diseases such as graft versus host rejection or rheumatoid arthritis. In addition, TNF exhibits antimalignant cell cytotoxicity in association with interferon. High concentrations of TNF-α are toxic to the host. The enhancement in the therapeutic index by decreasing toxicity or by increasing effectiveness is indeed needed. This may be possible through the mutations that reduce systemic cytotoxicity and increase TNF's effectiveness in selectively eliminating tumor cells. TNF-α is also implicated in physiological sleep regulation. TNF-related proteins such as receptor activator for nuclear factor κB ligand (RANKL) are required for

IL-17 is a pro-inflammatory cytokine. There are six family known members of IL-17. Also, we have just a little information of its biological functions, being the IL-17A and the IL-17F described recently [18]. IL-17–related cytokines play key roles in defense against extracellular pathogen, and their participation in the development of autoimmune diseases has drawn significant attention. Moreover, some of these molecules are involved in the amplification and perpetuation of pathological processes in many inflammatory diseases. However, the same cytokines can exert anti-inflammatory effects in specific settings, as well as play a key role in the control

IL-6 family is a group of cytokines and colony-stimulating factors (CSFs) that include IL-6, IL-27, IL-31, IL-35, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin (CT)-1, and cardiotrophin-like cytokine (CLC), among others [16, 17]. This cytokine family binds to its receptor, allowing a binding with the gp130 subunit [21, 22]. This binding allows dimerization of the subunit homogeneously or heterogeneously (either with the same subunit or cytokine receptor), creating a receptor complex. This complex allows associated proteins phosphorylation, such as Janus kinases (JAK) type 1, 2, and tyrosine kinase (TYK) 2, among others, which triggers a signaling pathway through phosphorylation toward types of signal transducer and activator of transcription (STAT) 1–6, forming another dimerization, homogeneous or

osteoclast differentiation necessary for bone resorption [16].

**12**

Type I cytokine family, also known as hematopoietins, is made up of several types of cytokines, including IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, IL-21, and granulocyte-macrophage colony-stimulating factor (GM-CSF), among others. This group of cytokines has α, β, and γ chain in common. IL-2, -4, -7, -9, -13, -15, and -21 have in common the γ chain (also known as IL2Rγ or CD132) for activation of JAK1/JAK3 and downstream STAT 1–5. While IL-3, -5, and GM-CSF share the common β chain (CSF2RB/CD131) for activation of the JAK/STAT pathway through interactions with JAK2 [3, 27], α chains do not activate signaling pathways but increase the binding affinity between the cytokine and β and γ subunit [3, 28], helping receptor specificity for gene expression [27]. While the receptor is more complex, there is more affinity of the cytokines of the receptor, which increases the signaling [27, 29]. The specificity of the receptor is conferred by α and β subunit, that in combination with γ subunit provides different stimulations. This means that the same cytokines can have different effects on the cell, depending on the receptor complexity; for example, IL-2 binds to its γ chain receptor (CD132) and β chain (IL-2Rβ), forming an intermediate affinity dimer, or also the binding of α chain (IL-2Rα), generating a high affinity. Phosphorylating tyrosine residues in JAKs, which lead to signaling to STAT5, prolonging and increasing its effect unlike the intermediate affinity [30]. Among the main functions of this cytokine family are the growth and differentiation of precursor leukocytes, as well as being modulators and initiators of the inflammatory response [3, 27].

#### **2.6 Type II superfamily**

The type II superfamily is composed of the subfamilies of interferons (IFNs) and IL-10. IFN family has the characteristic of inducing antiviral response in both hematopoietic and structural cells, serving as an essential mediator of cross talk between the immune system and host physiology during viral infections [3, 29]. This family is divided into three types INFs families: types I, II, and III.

Type I IFNs family is mainly composed of IFN-α and -β. IFN-α is expressed in leukocytes and IFN-β in fibroblasts, dendritic, and plasmacytoid cells. These IFNs have signaling pathways through JAK1 and TYK2 to phosphorylate STAT1 and STAT2 [29, 31]. These IFNs have a powerful proinflammatory effect and an antiviral response in immune and nonhematopoietic cells, as well as they can synergize with type II interferon (i.e., IFNγ) to potentiate Th1 lineage commitment by T-helper cells and cytotoxic activity by CD8<sup>+</sup> cells [3].

Type II IFNs family is composed only by IFN-γ, which is produced by active CD4+ and CD8+ T cells, NK cells, and macrophages by stimulation of IL-12, IL-18, and TNF-α [3, 29, 32]. IFN-γ has signaling pathways with STAT1 through JAK1 and JAK2 [29]. IFN-γ is mediator of interaction of innate and adaptive immune cells. IFN-γ promotes B-cell differentiation toward plasma cells immunoglobulin (Ig)-Gproduction. Also, IFN-γ induces phagocytosis through the antimicrobial potential activation on macrophages. IFN-γ increases the expression of major histocompatibility complex (MHC) I and II, molecules in antigen-presenting cells, promotes complement activation, and increases cytotoxic activity of T cells and differentiation Th1 cell differentiation for the clearance of infectious pathogens [3, 32].

Type III INFs family is composed by IFNλ-1 (IL-29), IFNλ-2 (IL-28A), and IFNλ-3 (IL-28B) [3, 29, 32]. IFNλ-1 and -2 regulate IFN expression [3], being structurally and functionally like them by sharing beta chain but with less intensity [32]. IFNλ-3 induces antiviral response in cells through STAT1 and STAT2 [3, 33].

IL-10 is a potent pro-inflammatory cytokine, which is produced by different cells such as monocytes, macrophages, Th2, and Treg cells. The IL-10 performs its functions through the activation of the STAT1, STAT3, PI3K, and p38 mitogenactivated protein kinases (MAPK) pathways. Among its most important functions are the suppression of Th1 cytokines, the classically activated/M1 macrophage inflammatory gene expression, and the presentation of antigen [3].
