**5. Other cytokines**

**4.2. Interleukin-2 family**

76 Autoantibodies and Cytokines

therapy [44, 63–65].

[44, 66, 67].

Th<sup>9</sup>

IL-4 is produced by Th<sup>2</sup>

factor. This cytokine is mainly produced by CD4+

autoimmune diseases and leukemia [44, 68].

potential treatment for this disease [44, 69, 70].

ties include the inhibition of cytokine production by Th1

by keratinocytes, skeletal muscle cells, monocytes and activated CD4+

IL-9 is mainly produced by Th2

The IL-2 cytokine family, also known as the common γ-chain family, is composed by ILs 2, 4, 7, 9, 15 and 21. All these ILs bind to the common γc receptor, also called CD132. These cyto-

IL-2 is the first member of the common γ-chain family, previously known as T cell growth

by dendritic cells and NKs. The IL-2R is composed by three subunits (CD25, CD122 and common γc), all necessary to binding to IL-2. IL-2 acts in the development of regulatory T (Treg) cells, as a B cell growth factor, stimulates antibody synthesis and promotes proliferation and differentiation of NK cells and T helpers. IL-2 has been extensively used as an anti-cancer

IL4-R type I, which binds only to IL-4 and is composed by CD124 (IL-4rα) and CD 132; and type II, which binds to IL-4 and to IL-13, and it consists in IL-4Rα and IL-13Rα1. These receptors are spread all over the human body. IL-4 is known to play several different roles, regulating allergic conditions and activating the immune response against extracellular parasites (B cell class switching to IgE). It is the main cytokine to stimulate development of Th2

Dupilimab is an IL-4 receptor antagonist approved in 2017 by FDA for treatment of eczema

IL-7 is a homeostatic cytokine. It can be found essentially in T cells, progenitors of B cells and bone marrow macrophages. As the other members of the family, its receptor (IL-7R) consists in the common γ-chain fraction, along with another unit, the IL-7Rα (CD127). IL-7 is involved in the survival and proliferation of thymocytes and in the development of naïve and memory B and T cells, mature T cells and NKs. Deficiencies related to IL-7 result in immunodeficiency,

and by mastocytes of asthmatic patients. Its receptor, IL-9R, is composed by the CD132 and IL-9Rα units. IL-9 is a potent growth factor for T cells and mastocytes, and some of it activi-

secretion by bronchial epithelium. Recently, a new subset of effector T cells was discovered,

IL-15 is structurally homologous to IL-2. The receptor, IL-15R, is composed by the CD132 subunit common to the family, and also by IL-15Rα and IL-2Rβ chains. IL-15 is produced

signals that trigger innate immunity. IL-15 has some identical functions to IL-2, such as T cell

cell, NK cell, and NKT-cell homeostasis. Increased levels of IL-15 were reported in autoim-

activation and stimulation of NK cell proliferation, but it also involved with CD8<sup>+</sup>

mune disorders, such as rheumatoid arthritis, psoriasis and celiac disease [44, 71].

, and it is believed that it is intimately related with IL-9 production. IL-9 is associated to allergic diseases and protection from helminthic infections. This cytokine can be found in elevated amounts in Hodgkin lymphoma, hence, IL-9 antagonists are being studied as a

and CD8<sup>+</sup>

cells, basophils, eosinophils and mastocytes. It has two receptors:

cells, but it is also expressed in less amounts by eosinophils

cells, IgE production, and mucus

T cells, in response to

memory

T cells, but can be also expressed

cells.

kines act as growth and proliferation factors for progenitors and mature cells [44, 63].

In addition to the aforementioned cytokines, other also deserves attention, such as chemokines. The chemokines represent a large family of structurally homologous cytokines that stimulate leukocytes movement and regulate the migration of them from the blood to tissues, in a process named chemotaxis. They control homeostatic immune cells, such as neutrophils, B cells, and monocytes, trafficking between the bone marrow, blood and peripheral tissues. Therefore, they can be classified as chemotactic cytokines [33, 72].

There are about 50 human chemokines, classified into 4 families according to the location of N-terminal cysteine residues. The two major families are CC and CXC chemokines, in which the cysteine residues are adjacent on CC family, and are separated by one amino acid on CXC family. In general, members of CC chemokines are chemotactic for monocytes, and a small subset of lymphocytes, while CXC chemokines are more specific for neutrophils. The bestknown chemokine is IL-8, or CXCL8, which belongs to the CXC chemokine family, and is responsible for neutrophil recruitment and for the maintenance of the inflammatory reaction. On the other hand, the monocyte chemoattractant protein-1 (MCP-1) or CCL2, and CCL11 or eotaxin, are examples of CC chemokines, which acts on recruitment of a variety of leukocytes, but especially monocytes, and eosinophils, respectively [33, 73, 74].

The chemokines receptors are expressed on all leukocytes and are divided in two groups: G protein-coupled receptors with seven-transmembrane α-helical segments, and atypical receptors, which appear to attenuate inflammation by scavenging chemokines, independently of G protein. Each receptor subtype is capable of binding to various chemokines of the same family, and a single chemokine can bind to more than one receptor. Despite of this factor, a lot of chemokines presents a great tissue and receptor specificity [72, 73].

Chemokines can be produced constitutively in various tissues, and are responsible for regulating the traffic of leucocytes, especially lymphocytes, through peripheral lymphoid tissues. However, the best-known activity of chemokines is the involvement on inflammatory reactions. Recruitment of macrophages, neutrophils and T cells to the site of inflammation is strongly stimulated by chemokines. In fact, they represent a secondary pro-inflammatory mediator that is induced by primary pro-inflammatory mediators, such as IL-1 or TNF. In general, members of the chemokines family induce recruitment of well-defined leukocyte subsets, differently of the classic leukocyte chemoattractants. They induce the movement of leukocytes, and consequently promote their migration to a specific local, by stimulating actin filaments [33, 72–74].

Beyond the involvement of the chemokines on acute inflammatory reactions, and the regulation of the traffic of leukocytes through peripheral lymphoid, independently of the presence of inflammation, some kind of chemokines can promote angiogenesis and wound healing, associated mostly with CXC family, while other are involved in the development of diverse nonlymphoid organs [73, 74]. They also have an important role in the priming of naive T cells, in effector and memory cell differentiation, and in regulatory T cell function [72].

that are responsible for the clinical manifestation, especially glomerulonephritis, arthritis and vasculitis. The peripheral blood lymphocytes of patient presents an excessive production and response to type 1 IFNs, but the involvement of this cytokines on the development of the diseases is still uncertain [33]. In these patients, for instance, serum IFN-α and IFN-αinduced gene expression are frequently observed, implying that the molecular pathogenesis of this condition is mediated by type I IFN. It has also been shown that IFN-γ serum levels are increased in SLE patients, and in mouse models, the receptor of this cytokine was necessary to the disease development. The massive amount of circulating IFN correlates to disease severity, which is likely to be triggered by excessive pDC activation. Recently, clinical trials evaluating anti-IFN-α monoclonal antibodies for SLE have been conducted, exhibiting promising results. Moreover, a trial evaluating a monoclonal antibody that binds IFN-γ was conducted, but no significant improvements in the efficacy outcome measures were observed. Additionally, a recent study demonstrated that keratinocytes may participate on the pathophysiological of the cutaneous manifestation of the SLE, by increasing cell apoptosis and producing proinflammatory cytokines, especially IL-23, IL-12, IL-6, IL-17, (Th17-related cytokines), IL-10

In parallel, another autoimmune disease widely studied that involves cytokines, besides several other factors, is the type 1 diabetes mellitus. This disease is characterized by pancreatic

reactive with islet antigens, the effect of cytotoxic T lymphocyte on lysis of islet cells, and local production of cytokines, especially TNF, IL-1, IL-21 and IFN-α. In some cases, the islets

Remaining islet cells often express class II MHC molecules, an effect of local production of INF-γ by the T cells [33, 73, 79]. The onset of young age of this disease may be associated with upregulation of growth factors, especially GM-CSF and IL-7. Other mediators overexpressed are the pro-inflammatory cytokine IL-1β, the regulatory cytokine IL-10, IL-27, and some Th17 cytokines (IL-17, IL-21, IL- 23). Additionally, patients that involve to ketoacidosis, a serious

In the same way, it stands out the rheumatoid arthritis, a chronic and systemic autoimmune disease described as a progressive disability on joints, particularly of the fingers, shoulders, elbows, knees and ankles that can promote systemic consequences like cardiovascular, pulmonary and skeletal disorders. It is characterized by the production of autoantibodies, like rheumatoid factor, cytokines, chemokines, hyperplasic synovium, osteoclastogensis and angiogenesis. The pro-inflammatory cytokines IL-1α/β, IL-8, IL-6, TNF-α, INF-y and some CSFs are responsible for the pathogenesis of this disease, and are involved with the intracellular molecular signaling pathway that causes chronic inflammation on synovial membrane. These cytokines, especially TNF-α, activates the leukocytes endothelial cells and synovial fibroblasts, and stimulates the production of collagenases that are responsible for the destruction of the cartilage, ligaments and tendons of the joints. Therefore, monoclonal antibody

TH 1 cells

cells.

79

and CD8<sup>+</sup>

Cytokines and Interferons: Types and Functions http://dx.doi.org/10.5772/intechopen.74550

β cells destruction, which it is due to hypersensitivity reactions mediated by CD4<sup>+</sup>

show cellular necrosis and lymphocytic infiltration, consisted of both CD4<sup>+</sup>

complication of the disease, have a tendency for higher IL-8 and IL-10 levels [80].

drugs, such as anti-TNF are approved for treatment of this disease [33, 75, 76, 81].

It is also believed that bone destruction in rheumatoid arthritis is due to overexpression of the TNF family cytokine receptor activator of nuclear factor KB (RANK), an essential mediator

and TFG-β [16, 30, 77, 78].

Besides chemokines, there are cytokines that stimulates hematopoiesis, such as the colonystimulating factors (CSFs), which contributes to the growth of progenitors of monocytes, neutrophils, eosinophils and basophils, as well as activating macrophages. Immune and inflammatory reactions uses leukocytes, due to the recruitment induced by some kinds of cytokines, so new must be produced [73, 74]. Additionally, the GM-CSF (granulocyte-macrophage colony-stimulating factor) and M-CSF (macrophage colony-stimulating factor) have, like some other cytokines, a pro-inflammatory action, and exhibit a connexon between the expression of them and TNF, IL-1, IL-23 and IL-17 [75].

Finally, other cytokines can be highlighted: TGF-β, LIF, Eta-1 and oncostatin M. The TGF-β is responsible for the chemoattraction of monocytes and macrophages, but also it has an antiinflammatory effect, by inhibiting the lymphocyte proliferation. LIF and oncostatin M induce the production of acute-phase protein, while Eta-1 stimulates the production of IL-2, and inhibits the production of IL-10 [73].
