**3. Cytokine profile in bacterial infections**

During a bacterial infection in the host, a nonspecific and immediate immune response is initiated to eliminate the pathogen, and this nonspecific response involves the recruitment of neutrophils, macrophages and dendritic cells, complement activation, and cytokine production [34]. This response can inhibit or limit microbial growth but also can cause host damage, and so it is necessary to keep this response under control; to achieve this, the host performs some strategies, including the production of cytokines. These molecules play an important role in intercellular communication and coordinate the innate and adaptive response [35].

In microbial infections, the pattern-recognition receptors (PRRs) recognize several PAMPs [36] such as DNA, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and 5′-triphosphate RNA, as well as lipoproteins, surface glycoproteins, membrane components peptidoglycans, lipoteichoic acid (LTA), lipopolysaccharide (LPS), and glycosyl-phosphatidyl-inositol. The recognition of PAMPs by PRRs leads to the activation of NF-κB and/or MAPK [37] to produce several cytokines such as IL-1α, IL-1β, TNFα, IFN-γ, IL-12, and IL-18, being TNF-α and IL-1β the main inflammatory mediators, since they play an important role in mediating the local response through cellular activation. The inflammatory response that occurs in the presence of an infection consists of several protective effector mechanisms that promote the microbicidal functions and in turn stimulate adaptive immunity, which contributes to reduce the damage of the tissues [38] (**Figure 1**).

IL-1β is a cytokine that is inducible through the activation of PRRs such as TLRs, by microbial products or damaged cell factors [39], once the recognition of the ligands through the receptors activates the downstream signaling pathways activating the NF-κB, activator protein (AP)-1, MAPK, and type I IFNs pathways, resulting in an upregulation of inflammatory mediators, as well as chemotactic factors [40]. IL-1β is synthesized as a precursor peptide (pro-IL-1β) that is cut to generate its mature form (mIL-1β); this process involves caspase 1, and the proenzyme (procaspase-1) requires it to be cut by the inflammasome, which is a multimeric cytosolic protein complex, composed of NLR family-pyrin domain containing 3 (NALP3) and the adapter protein containing CARD (ASC) and caspase-1; once IL-1β is cut by this complex, it binds to the IL-1R1 receptor, thus initiating the signaling that induces

**15**

of CD4+

**Figure 1.**

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

the expression of adhesion molecules in the endothelial cells and promotes the recruitment of neutrophils to the site of inflammation, as well as of the monocytes. It also has a potent stimulatory effect on phagocytosis, and it produces a chemotactic effect on leukocytes and induces the production of other inflammatory mediators of the lipid type, as well as other cytokines [41]. In vivo studies show that IL-1β is an important cytokine for the host defense against some microbial pathogens. During infection with *Staphylococcus aureus,* it was shown that the interaction of IL-1β with its receptor IL-1R plays an important role in the recruitment of neutrophils, suggesting that IL-1β is crucial for host defense against *S. aureus* and this can be transpolar

*Cytokines profile in bacterial infections. In response to bacterial infection, the IL-1 family cytokines, such as IL-1β, potently induces the expression of adhesion molecules in the endothelial cells and promotes the recruitment of neutrophils to the site of inflammation. TNF-α plays an important role through the recruitment of neutrophils and macrophages, besides inducing the expression of proinflammatory mediators to the site of infection. Th17 cells produce IL-17A, which induces the production of inflammatory mediators such as IL-1β, IL-6, GM-CSF, G-CSF, and TNF-α, as well as adhesion molecules. IL-18 also promotes the secretion of other proinflammatory cytokines like TNF-α, IL-1β, IL-8, and GM-CSF and consequently enhancement, migration,* 

Another cytokine that accompanies the IL-1β response is TNF-α, and this cytokine is produced initially during endotoxemia, as well as in response to some microbial products. TNF-α shares with IL-6 an important inflammatory property, that is, the induction of acute phase reactant protein by the liver [43]. In vivo studies show that TNF-α plays an important role in mediating clearance through the recruitment of neutrophils and macrophages to the site of infection after a bacterial intraperitoneal challenge [44], followed by an increase in the expression of COX-2, as well as inducible nitric oxide synthase (iNOS), which leads to the production of prostaglan-

During bacterial infections, the IL-17 is another important cytokine produced. IL-17A plays an important role in the defense of the host against extracellular bacteria. The cells that are characterized mainly by producing IL-17 are a subpopulation

of cytokines, including transforming growth factor (TGF)-β and IL-6, IL-21 and TGF-β, or IL-1, IL-6, and IL-23 [46, 47]. The protective capacity of IL-17A against infectious agents can be mediated through several mechanisms, among these is the ability of IL-17A in the barrier surfaces to induce the production of inflammatory

T cells, and their differentiation and maturation are favored by a mixture

din (PG)-E2 and NO to eradicate the pathogen and recover homeostasis [45].

to infections induced by other microorganisms [42].

*and activation of neutrophils during infections.*

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

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

#### **Figure 1.**

*Immune Response Activation and Immunomodulation*

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].

During a bacterial infection in the host, a nonspecific and immediate immune

In microbial infections, the pattern-recognition receptors (PRRs) recognize several PAMPs [36] such as DNA, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and 5′-triphosphate RNA, as well as lipoproteins, surface glycoproteins, membrane components peptidoglycans, lipoteichoic acid (LTA), lipopolysaccharide (LPS), and glycosyl-phosphatidyl-inositol. The recognition of PAMPs by PRRs leads to the activation of NF-κB and/or MAPK [37] to produce several cytokines such as IL-1α, IL-1β, TNFα, IFN-γ, IL-12, and IL-18, being TNF-α and IL-1β the main inflammatory mediators, since they play an important role in mediating the local response through cellular activation. The inflammatory response that occurs in the presence of an infection consists of several protective effector mechanisms that promote the microbicidal functions and in turn stimulate adaptive immunity, which contributes to reduce the damage of the tissues [38] (**Figure 1**). IL-1β is a cytokine that is inducible through the activation of PRRs such as TLRs,

by microbial products or damaged cell factors [39], once the recognition of the ligands through the receptors activates the downstream signaling pathways activating the NF-κB, activator protein (AP)-1, MAPK, and type I IFNs pathways, resulting in an upregulation of inflammatory mediators, as well as chemotactic factors [40]. IL-1β is synthesized as a precursor peptide (pro-IL-1β) that is cut to generate its mature form (mIL-1β); this process involves caspase 1, and the proenzyme (procaspase-1) requires it to be cut by the inflammasome, which is a multimeric cytosolic protein complex, composed of NLR family-pyrin domain containing 3 (NALP3) and the adapter protein containing CARD (ASC) and caspase-1; once IL-1β is cut by this complex, it binds to the IL-1R1 receptor, thus initiating the signaling that induces

response is initiated to eliminate the pathogen, and this nonspecific response involves the recruitment of neutrophils, macrophages and dendritic cells, complement activation, and cytokine production [34]. This response can inhibit or limit microbial growth but also can cause host damage, and so it is necessary to keep this response under control; to achieve this, the host performs some strategies, including the production of cytokines. These molecules play an important role in intercellular

communication and coordinate the innate and adaptive response [35].

**3. Cytokine profile in bacterial infections**

**14**

*Cytokines profile in bacterial infections. In response to bacterial infection, the IL-1 family cytokines, such as IL-1β, potently induces the expression of adhesion molecules in the endothelial cells and promotes the recruitment of neutrophils to the site of inflammation. TNF-α plays an important role through the recruitment of neutrophils and macrophages, besides inducing the expression of proinflammatory mediators to the site of infection. Th17 cells produce IL-17A, which induces the production of inflammatory mediators such as IL-1β, IL-6, GM-CSF, G-CSF, and TNF-α, as well as adhesion molecules. IL-18 also promotes the secretion of other proinflammatory cytokines like TNF-α, IL-1β, IL-8, and GM-CSF and consequently enhancement, migration, and activation of neutrophils during infections.*

the expression of adhesion molecules in the endothelial cells and promotes the recruitment of neutrophils to the site of inflammation, as well as of the monocytes. It also has a potent stimulatory effect on phagocytosis, and it produces a chemotactic effect on leukocytes and induces the production of other inflammatory mediators of the lipid type, as well as other cytokines [41]. In vivo studies show that IL-1β is an important cytokine for the host defense against some microbial pathogens. During infection with *Staphylococcus aureus,* it was shown that the interaction of IL-1β with its receptor IL-1R plays an important role in the recruitment of neutrophils, suggesting that IL-1β is crucial for host defense against *S. aureus* and this can be transpolar to infections induced by other microorganisms [42].

Another cytokine that accompanies the IL-1β response is TNF-α, and this cytokine is produced initially during endotoxemia, as well as in response to some microbial products. TNF-α shares with IL-6 an important inflammatory property, that is, the induction of acute phase reactant protein by the liver [43]. In vivo studies show that TNF-α plays an important role in mediating clearance through the recruitment of neutrophils and macrophages to the site of infection after a bacterial intraperitoneal challenge [44], followed by an increase in the expression of COX-2, as well as inducible nitric oxide synthase (iNOS), which leads to the production of prostaglandin (PG)-E2 and NO to eradicate the pathogen and recover homeostasis [45].

During bacterial infections, the IL-17 is another important cytokine produced. IL-17A plays an important role in the defense of the host against extracellular bacteria. The cells that are characterized mainly by producing IL-17 are a subpopulation of CD4+ T cells, and their differentiation and maturation are favored by a mixture of cytokines, including transforming growth factor (TGF)-β and IL-6, IL-21 and TGF-β, or IL-1, IL-6, and IL-23 [46, 47]. The protective capacity of IL-17A against infectious agents can be mediated through several mechanisms, among these is the ability of IL-17A in the barrier surfaces to induce the production of inflammatory

mediators such as IL-1β, IL-6, GM-CSF, granulocyte colony stimulating factor (G-CSF), and TNF-α, as well as adhesion molecules. IL-17A also induces the production of chemotactic factors, such as chemokine-(C-C motif)-ligand (CCL)-2, CCL7, CXCL1, CXCL2, CXCL5, and CXCL8, responsible for recruiting neutrophils and monocytes, as well as the CCL20 that is involved in the recruitment of dendritic cells, with the aim of eliminating the extracellular pathogen [48]. In vivo and in vitro studies show that signaling through TLR4 is the main mechanism by which IL-17 is induced in response to *Klebsiella pneumoniae* infection, which induces an upregulation of granulopoietic cytokines involved in the recruitment of neutrophils [49]. In mice lacking the IL-17 receptor, the recruitment of neutrophils decreased, the bacterial load increased, and survival was compromised. Whereas overexpression of IL-17 through an adenovirus, resulted in the production of cytokines mainly, macrophage inflammatory protein (MIP)-2, G-CSF, TNF-α, and IL-1β, increasing the recruitment of neutrophils, bacterial clearance and finally survival after infection with K. pneumoniae [50]. And finally, PGE2 increases the expansion of Th17 cells in an IL-1β dependent manner, thus favoring the recruitment of these cells to the site of damage. In vitro studies show that Th17 cells in the presence of PGE2 increase the production of CCL20, thus favoring the control of infection [51].

IL-18 also promotes the secretion of other proinflammatory cytokines like TNF-α, IL-1β, IL-8, and GM-CSF and consequently enhancement, migration, and activation of neutrophils during infections. IL-18 increases the cytotoxic activity and proliferation of CD8+ T and NK cells, as well as promotes the secretion of inflammatory mediators of the type TNF-α, IL-1β, IL-8, and GM-CSF, which will activate neutrophils, thus increasing their migration [38]. During a bacterial infection, IL-18 plays an important role, since it induces IFN-γ production of NK cells [52]. The IFN-γ that is produced activates macrophages and produces cytokines that induce antimicrobial pathways against intracellular and extracellular pathogens [53]. Infection with strains of lactobacillus nonpathogenic and with streptococcus pyogenes induces the expression of IL-1β, IL-6, TNF-α, IL-12, IL-18, and IFN-γ, suggesting that this type of bacterial strains induces Th1 type cytokines [54].
