**3. Tumor necrosis factor**

that participate in T cells activation, therefore initiating the adaptive immune response. After being produced and entering the infected site, the effector T cells become, in turn, the main source of IFN-γ and cell-mediated cytotoxicity. Besides the effects on host defense, IFN-γ is

Type III IFN (IL-28/29 or IFN-λ), likewise type I IFN, present antiviral activity. Type III IFN is subdivided in IFN-λ1 and IFN-λ2/3, which are expressed in identical patterns. The signaling pathway related to IFN-λ is similar to IFN-α/IFN-β, involving mechanisms relying on IRFs and NF-κB actions, with the last one playing an essential role in regulating type III IFN expression. Nevertheless, the expression of IFN-λ is more flexible when compared to type I IFN, once it also involves independent actions of NF-kB and IRFs, allowing the production of this cytokine in response to a wider range of stimuli. Most classes of virus and some bacterial products induce IFN-λ expression, and almost all cell types, mostly pDCs, produce type III IFN after virus infection. However, different from the other types of IFN, macrophages are not involved in IFN-λ expression. Regarding biological activities, IFN-λ acts as the first line in host defense against viral infections, besides regulating innate and adaptive immune responses. Recently, a new member of the Interferon Lambda family was identified, the IFN-λ4. This cytokine presents strong antiviral activity and has been recently described to be related to hepatitis C treatment failure. Several *in vivo* studies have shown that IFN-λ can be developed as a potent antiviral agent, covering a wide spectrum of viral infections, with the additional

benefit of not promoting the unwanted pro-inflammatory effects of IFN-α [6, 27–29].

The first sign that type I IFN was somehow involved with human autoimmune diseases came from the observation of an increased incidence of autoantibodies and autoimmune diseases after type I IFN treatment. Hence, when considering the indication of IFN-α therapy for some conditions (e.g., hepatitis C virus infection), it is important to scrutinize the presence of autoantibodies in the patient, since they may increase the risk for autoimmune disease development with this kind of treatment [14]. As previously mentioned, pDCs are responsible for producing high levels of type I IFN in response to nucleic acid-containing immune complexes through the activation of TLRs 7 and 9 [11]. These immune complexes are prevalent in autoimmune conditions, such as systemic lupus erythematosus (SLE), which makes this process highly relevant for the development of autoimmunity. It has been described that, in autoimmune diseases, several key immune effector cells, such as B cells, T effector cells and regulatory T cells are modulated by IFN-α. Hence, type I IFN plays a substantial role in this kind of condition [16]. Regarding type II IFN, IFN-γ may contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis and type I diabetes mellitus. The role of this cytokine in autoimmune diseases (both in promoting and suppressing the condition) has been shown in several mouse models. The administration of IFN-γ at very early stages of experimental autoimmune encephalomyelitis exacerbates the disease, while its administration at a later stage reduces disease severity. Hence, the absence of biomarkers that could indicate the best stage of the disease to initiate IFN-γ treatment consists in a limiting factor for its therapeutic use [25, 26, 30]. This subject will be reported in the topic "Cytokines

**2.3. Interferons and related diseases**

70 Autoantibodies and Cytokines

and autoantibodies".

also involved in the protection against tumor development [5, 26].

Tumor necrosis factor (TNF) is a cytokine that had the name derived from it discovery in 1975 as a molecule that caused in vitro necrosis of tumors. Shortly thereafter, it was observed that TNF expression was promoted by immune system cells. These discoveries were important to a posterior characterizing of the TNF superfamily and the TNF receptor superfamily, which has more than 40 members, being the most outstanding TNF-α (commonly named as TNF) and TNF-β (also named Iymphotoxin), but also including cytokines and membrane proteins that have similar sequence homologies and a homotrimeric pyramidal structure (e.g. CD40 ligand, FAS ligand, OX40 ligand, GITR ligand and other several proteins). The binding of this family of cytokines with their respective receptors triggers especially inflammatory reactions [33–37] .

TNF-β, a type II transmembrane protein, is an important key in the development of lymph nodes and Peyer's patches, and also for the maintenance of secondary lymphoid organs. The expression of TNF-β is mainly stimulated by lymphocytes. TNF-α will be better described in the following topics [38, 39].

Although it were discovered many receptors along the decades, two are best known: TNFR1 (55 kD) and TNFR2 (75 kD). Both receptors are plasma membrane trimmers, while TNFR1 is expressed by most human cells and TNFR2 is mainly produced by immune system cells. It is important to mention that TNFR2 have a higher affinity to TNF. They are related to inflammatory reactions, so that a cytokine bind to the receptor, it induces the recruitment of proteins that are important for the process [35, 40] .

### **3.1. Expression and structure of tumor necrosis factor alpha**

The production of this cytokine is performed by different cells from the immune system, which includes T cells, NK cells, macrophages and monocytes. The stimulus for TNF expression includes different factors, such as bind to pathogen lipopolysaccharide (LPS) and other parts with toll-like receptors (TLRs), and also by other cytokines, highlighting IFN-y [33, 35].

It is primary secreted as a nonglycosylated type II membrane protein arranged as homotrimer. TNF membrane releases a trimeric soluble cytokine (a polypeptide that weighs around 17-kDa with triangular pyramid shape) through proteolytic cleavage by metalloprotease TNF-converting enzyme, and this is the circulating form that is found in blood plasma, and that allows a potent capacity to displacement in the body, thus it endocrine function. It is not well defined but from three of these circulating TNF it is possible to polymerize them forming one 51-kD polypeptide which facilitates the binding of the cytokine with three receptors simultaneously [37, 41, 42].

**4. Interleukins**

Interleukins (ILs) are a group of secreted proteins with diverse structures and functions. These proteins bind to receptors and are involved in the communication between leukocytes. They are intimately related with activation and suppression of the immune system and cell

Interleukins are named as IL plus a number. Previously, different names were used to refer to the same IL. For instance, IL-1 was called lymphocyte-activating factor, mitogenic protein or T cell replacing factor III. In order to standardize the nomenclature, in 1979, during the Second International Lymphokine Workshop, the term interleukin was introduced. After that, the interleukins started being named consecutively according to the date of their discovery [44, 46, 47]. There have been identified 40 interleukins so far and some of them are further divided into subtypes (e.g. IL-1α, IL-1β). These ILs are grouped in families based on sequence homology

In this section, a brief description of various ILs will be presented. Focus will be given to the

Interleukin-1 family is composed by 11 cytokines: 7 ligands with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ), 3 receptor antagonists (IL-1Ra, IL-36Ra and

The interleukin-1 family started with only two components: IL-1α, IL-1β. Over the years, new IL with similar behavior and/or structure were discovered and added to the family. All the agonists members of this family show pro-inflammatory activity. These cytokines share a common C-terminal three-dimensional structure with a typical β-trefoil fold consisting of 12-β-strands connected by 11 loops, and have identical positioning of certain introns. Considering that, it is plausible to affirm that they probably arose from the duplication of a

All members of the family except IL-18 and IL-33 have genes encoding on chromosome 2 in a 400 kb region in human species. Despite the fact that all the cytokines are extracellular, they are synthesized without a hydrophobic leader sequence and are not secreted via reticulum endoplasmic-Golgi pathway, with the exception of IL-1Ra. The secretion mechanism of the other members of the family is still not known. These cytokines bind to closely related receptors, and many of the encoding genes are clustered in a short region of chromosome 2. The receptors contain extracellular immunoglobulin domains and a toll/IL-1 receptor (TIR)

In order to become active, both IL-1α and IL-1β bind to the ligand-binding chain type I (IL-1R1). Then, the co-receptor, termed the accessory protein (IL-1RAcP), is recruited, and together they

T lymphocytes, monocytes,

Cytokines and Interferons: Types and Functions http://dx.doi.org/10.5772/intechopen.74550 73

division. The interleukins are synthesized mostly by helper CD4+

and receptor chain similarities or functional properties [5, 44, 48, 49].

IL-38) and 1 anti-inflammatory cytokine (IL-37) [44, 50].

macrophages and endothelial cells [5, 44, 45].

families of interleukins 1 and 2.

**4.1. The interleukin-1 family**

common ancestral gene [45, 51, 52].

domain in the cytoplasmic portion [45, 52].
