**6. Cytokine profile in parasitic infections**

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 importance for human health.

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

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

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

*Immune Response Activation and Immunomodulation*

**5.3 Cytokines' role in viral infection**

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

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

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

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-inflamma-

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

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

in the surface of the cell [94]. These activated cells can

from circulating system through inflammation process (**Figure 3**).

immunomodulatory and anti-inflammatory actions [95].

**20**

TGF-β [103].

TNF-α [95].

tory actions [100].

expression of CD11b<sup>+</sup>

cytokine-activated macrophages are central to the innate response to intracellular parasites. Innate cytokine and dendritic cell responses also play a critical role in the induction of adaptive immunity [119].

During the initial stage of parasitic protozoan infections, intestinal epithelial cells (IECs) bind and recognize PAMPs through PRRs [120] such as TLR-2 and TLR-4 [121], which activates NF-κB and leads to the production of proinflammatory cytokines [122], including IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α [123, 124], which induces the activation of a Th1 type response [125]. IFN-γ is involved in clearance of infection, through the activation of neutrophils and macrophages (**Figure 4**) [126–132]. It has been also shown that IFN-γ-producing CD4+ T cells are involved protection in vaccinated mice [133]. Several studies suggest a role for IFN-γ in the pathogenesis of parasitic protozoan infections. In both humans and animal models, the production of high levels of IFN-γ is associated with resistance to infection [134–136], while low levels of IFN-γ are associated with an increased susceptibility to infection. Therefore, it is considered highly probable that IFN-γ provides protection against infection by activation of neutrophils and/or macrophages [125]. The production of reactive oxygen species (ROS) and NO through the complex of NADPH oxidase and iNOS, respectively, plays a critical role in the elimination of protozoan parasites [131, 132]. In experimental studies, infection protection was mediated by IFN-γ from NK T cells (NKT), while TNF-α is produced by increased tissue damage [137, 138], together with IL-1 and IL-8 [139] (**Figure 4**).

On the other hand, the antigenic exposure of protozoan parasites activates a Th2-type immune response by the host, inducing the production of anti-inflammatory cytokines such as IL-4, IL-10 [125], IL-5 and IL-13, which try to attenuate the Th1 type response characterized also by the INF-γ production, leading to upregulation of Th2 cytokine responses (IL-4, IL-5, and IL-13) and Th17 (IL-17), suppressing the production of Th1 cytokines [140] (**Figure 4**). In addition, another cytokine of anti-inflammatory importance is TGF-β, which acts in a synergistic manner to counteract this Th1 type response, activating macrophages which produce

#### **Figure 4.**

*Cytokines profile in parasitic protozoan infections. The immune defense mechanisms against protozoan parasites involve several immune cells such as neutrophils, macrophages, NK cells, and CD4+ T cells. These cells are capable to produce proinflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, promoting type 1 immune response. Likewise, protozoan parasites activate a Th2-type immune response, producing anti-inflammatory cytokines such as IL-4, IL-10, IL-5, and IL-13, suppressing the production of Th1 cytokines.*

**23**

**Figure 5.**

*expulsion.*

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

NO, through iNOS, for the elimination of the parasite [138].  Parasitic helminth infections are a major public health problem worldwide due

The immune response against helminth parasites is characterized by the induction of an early Th1-type immune response, with the subsequent predominance of a Th2 type immune response, resulting in a mixture of both Th1/Th2 immune

have a key role in the establishment of the cytokine environment during helminth parasite infection, thus directing their differentiation either by suppressing or favoring the inflammatory response at the intestinal level, which is crucial for the

PAMPs derived from helminth parasites induce the activation and maturation of dendritic cells [147, 148], promoting the development of the Th1 immune response [149], which results in a significant increase of Th1 cytokines such as IL-12 [150–152], INF-γ [149–153], IL-1β [152, 154], and TNF-α [150–152, 155] (**Figure 5**). However, in recent years, several studies have shown that this immune response of Th1 type favors infection by helminth parasites. On the one hand, IL-12 and INF-γ are two important cytokines against infection by helminth parasites, since they participate in the polarization of the Th1 type immune response [149–151, 153]. However, exogenous IL-12 is capable of suppressing intestinal mastocytosis, delaying the parasite expulsion, and increasing the parasite burden at the muscular level [156]. INF-γ induces the expression of iNOS, activates transcription factors such as NF-κB [157], and regulates the production of pro-inflammatory cytokines such as TNF-α [158]. Studies have shown that TNF-α is a cytokine that is produced during

*Cytokines profile in parasitic helminth infection. The immune response against helminth parasites is characterized by the induction of an early Th1 type immune response, which results in a significant increase of Th1 cytokines such as IL-12, INF-γ, IL-1β, and TNF-α. Then, there is a subsequent predominance of a Th2 type immune response characterized by the release of IL-4, IL-5, IL-10, and IL-13 favoring helminth parasites*

T cells [145]. The CD4+

T cells

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

Th2-type cytokine response mediated mainly by IL-4.

responses [143, 144], which depend on the CD4+

elimination of the parasite [146] (**Figure 5**).

**6.2 Immune system activation by parasitic helminth infection**

to their ability to cause great morbidity and socioeconomic loss [141, 142].

NO, through iNOS, for the elimination of the parasite [138]. Therefore, Th1-type cytokine response is characterized mainly by the production of IFN-γ, whereas susceptibility to tissue damage by protozoan parasites is critically dependent on a Th2-type cytokine response mediated mainly by IL-4.