**4. Cytokine profile in fungal infections**

As well as the response to bacteria, the response against fungi also requires coordination of the innate and adaptive immune system. The innate immune system performs its effect through the cells that have the phagocytic and antigen presenting function. These cells include neutrophils, macrophages, and dendritic cells [55]. The recognition of pathogens by the immune system involves four class of PRRs: TLRs, C-type lectin receptors (CLRs), nucleotide-binding oligomerization domainlike (NOD-like) receptors (NLRs), and retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) [56]. The CLRs, especially Dectin-1 and 2, play an important role in the pathogen recognition from *Candida spp.*; this is because the cell wall is made up of mannoproteins with O-glycosylated oligosaccharide and N-glycosylated polysaccharide moieties, with an inner layer of chitin and β (1, 3) and β (1, 6) glucans are recognized and initiate a downstream signaling through these receptors, which leads to activation of the transcription factor NF-κB and other signaling pathways that induce the production of pro-inflammatory cytokines such as IL-6, IL-1β, and IL-23 that induce the Th17 cytokines [57] (**Figure 2**).

The recognition of fungi by phagocytic cells occurs mainly through the detection of cell wall components such as mannan, β-glucan, phosphocholine, β-1,6 glucan, and even internal components such as DNA can be recognized [58, 59]. The recruitment and activation of phagocytic cells are mediated through the induction

**17**

**Figure 2.**

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

of proinflammatory cytokines, chemokines, and complement components. Fungi are killed by oxidative and nonoxidative mechanisms and antimicrobial peptides. These activities are influenced by the action of cytokines such as IFN-γ [59]. This cytokine produced mainly by T and NK cells stimulates the migration, adherence, and phagocytosis of neutrophils and macrophages and production of opsonizing antibodies and maintains a Th1 response as a protective response against fungi. It also induces a classical activation of macrophages that is important to stop the growth of intracellular fungal pathogens [60]. The Th1 response occurs through the release of proinflammatory cytokines IFN-γ, TNF-α, and GM-CSF, increasing the permeability in the tissue, as well as the phagocytic cells at the site of infection

*Cytokines profile in fungal infections. The PRRs recognize fungal PAMPs and initiate a downstream signaling, which leads to the activation of the NF-κB and other signaling pathways inducing the production of cytokines such as IL-6, IL-1β, IL-12, TNF-α, GM-CSF, IFN-γ, and IL-23. These cytokines induce the differentiation of Th1 and Th17 immune responses against fungi infection, stimulating the migration, adherence, and* 

Another important cytokine in immunity against fungi is IL-12, and this cytokine is considered the main cytokine that induces IFN-γ production. IL-12 is produced by monocytes, macrophages, and dendritic cells, in response to microbial products, and acts on NK and T cells to induce IFN-γ. On the other hand, the late secretion of IL-12 in the lymph nodes induces naive T cells to produce IFN-γ and therefore amounting a Th1 response is promoted [62]. The ability of IFN-γ to increase the production of IL-12 forms a positive feedback during the inflammatory process and the Th1 response, and this interferon in turn activates monocytes and macrophages to induce the production of IL-12 [63] (**Figure 2**). Studies in Il12p35<sup>−</sup>/<sup>−</sup> and IFN-γ−/<sup>−</sup> mice show an increase in susceptibility to infections with *Candida albicans*, and this suggests that IL-12 and the Th1 responses play an important role in controlling *Candida* infection [64]. On the other hand, neutrophils kill the extracellular and intracellular fungi through effector mechanism that includes the production of reactive oxygen and nitrogen species, as well as the release of hydro-

lytic enzymes and their granules containing antimicrobial peptides [65].

IL-23 is a member of the IL-12 family and plays a central role in the expansion of Th17 cells as well as their function, composed of a p19 and p40 subunit that shares it with IL-12 [66, 67]. IL-23 is produced primarily by dendritic cells, the binding of β-glucan to Dectin-1 activates the syk-CARD-9 signaling pathway leading to the production of IL-23, which promotes the Th17 response, through the differentiation

to efficiently clean the infection [61] (**Figure 2**).

*phagocytosis of neutrophils and macrophages.*

*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 2.**

*Immune Response Activation and Immunomodulation*

ity and proliferation of CD8+

**4. Cytokine profile in fungal infections**

IL-23 that induce the Th17 cytokines [57] (**Figure 2**).

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 activ-

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].

As well as the response to bacteria, the response against fungi also requires coordination of the innate and adaptive immune system. The innate immune system performs its effect through the cells that have the phagocytic and antigen presenting function. These cells include neutrophils, macrophages, and dendritic cells [55]. The recognition of pathogens by the immune system involves four class of PRRs: TLRs, C-type lectin receptors (CLRs), nucleotide-binding oligomerization domainlike (NOD-like) receptors (NLRs), and retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) [56]. The CLRs, especially Dectin-1 and 2, play an important role in the pathogen recognition from *Candida spp.*; this is because the cell wall is made up of mannoproteins with O-glycosylated oligosaccharide and N-glycosylated polysaccharide moieties, with an inner layer of chitin and β (1, 3) and β (1, 6) glucans are recognized and initiate a downstream signaling through these receptors, which leads to activation of the transcription factor NF-κB and other signaling pathways that induce the production of pro-inflammatory cytokines such as IL-6, IL-1β, and

The recognition of fungi by phagocytic cells occurs mainly through the detection of cell wall components such as mannan, β-glucan, phosphocholine, β-1,6 glucan, and even internal components such as DNA can be recognized [58, 59]. The recruitment and activation of phagocytic cells are mediated through the induction

T and NK cells, as well as promotes the secretion

**16**

*Cytokines profile in fungal infections. The PRRs recognize fungal PAMPs and initiate a downstream signaling, which leads to the activation of the NF-κB and other signaling pathways inducing the production of cytokines such as IL-6, IL-1β, IL-12, TNF-α, GM-CSF, IFN-γ, and IL-23. These cytokines induce the differentiation of Th1 and Th17 immune responses against fungi infection, stimulating the migration, adherence, and phagocytosis of neutrophils and macrophages.*

of proinflammatory cytokines, chemokines, and complement components. Fungi are killed by oxidative and nonoxidative mechanisms and antimicrobial peptides. These activities are influenced by the action of cytokines such as IFN-γ [59]. This cytokine produced mainly by T and NK cells stimulates the migration, adherence, and phagocytosis of neutrophils and macrophages and production of opsonizing antibodies and maintains a Th1 response as a protective response against fungi. It also induces a classical activation of macrophages that is important to stop the growth of intracellular fungal pathogens [60]. The Th1 response occurs through the release of proinflammatory cytokines IFN-γ, TNF-α, and GM-CSF, increasing the permeability in the tissue, as well as the phagocytic cells at the site of infection to efficiently clean the infection [61] (**Figure 2**).

Another important cytokine in immunity against fungi is IL-12, and this cytokine is considered the main cytokine that induces IFN-γ production. IL-12 is produced by monocytes, macrophages, and dendritic cells, in response to microbial products, and acts on NK and T cells to induce IFN-γ. On the other hand, the late secretion of IL-12 in the lymph nodes induces naive T cells to produce IFN-γ and therefore amounting a Th1 response is promoted [62]. The ability of IFN-γ to increase the production of IL-12 forms a positive feedback during the inflammatory process and the Th1 response, and this interferon in turn activates monocytes and macrophages to induce the production of IL-12 [63] (**Figure 2**). Studies in Il12p35<sup>−</sup>/<sup>−</sup> and IFN-γ−/<sup>−</sup> mice show an increase in susceptibility to infections with *Candida albicans*, and this suggests that IL-12 and the Th1 responses play an important role in controlling *Candida* infection [64]. On the other hand, neutrophils kill the extracellular and intracellular fungi through effector mechanism that includes the production of reactive oxygen and nitrogen species, as well as the release of hydrolytic enzymes and their granules containing antimicrobial peptides [65].

IL-23 is a member of the IL-12 family and plays a central role in the expansion of Th17 cells as well as their function, composed of a p19 and p40 subunit that shares it with IL-12 [66, 67]. IL-23 is produced primarily by dendritic cells, the binding of β-glucan to Dectin-1 activates the syk-CARD-9 signaling pathway leading to the production of IL-23, which promotes the Th17 response, through the differentiation 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 β-defensin 3 [66, 69].
