Cytokines are low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune systems. They are small cell-signalling regulatory proteins or glycoprotein's used extensively in intercellular communication to regulate the development of immune effector cells and also direct effector functions. Cytokines bind to target cell with specific receptors and triggers signal-transduction pathways that alters gene expression in the target cells. Cytokines exhibit the attributes of pleiotropy, redundancy, synergy, antagonism, and cascade induction, which allows them to co-ordinate and regulate cellular activity. Although a variety of cells can secrete cytokines, the two principal producers are the TH cell and the macrophage. Cytokines released from these two cell types activate an entire network of interacting cells. Cytokines have numerous biological functions like mediating cellular and humoral responses, inflammatory response induction, hematopoiesis regulation, cellular proliferation control and differentiation, and healing of wounds.
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Cytokines are intercellular messenger proteins produced by cells to interact and perform incredible variety of functions with cells of the immune system by regulating the body's response to infection and disease. It also mediate normal cellular processes in the body(Feldmann and Maini 2008). Cytokines are released by cells into the blood circulation or directly into tissue. These cytokines identify immune cells and bind to them with its receptors and this interaction stimulates specific responses by the target cells. Cytokines regulates response to infection, immune responses, inflammation, and trauma in host. Fig 1 shows the various cytokines released on exposure to antigen. Some cytokines make disease worse by inducing proinflammatory response, whereas others reduce inflammation and promote healing which are anti-inflammatory cytokines. Proinflammatory cytokines up-regulate a cascade of gene products that mediate inflammation like the chemokines, endothelial cell adhesion molecules and inducible nitric oxide synthase. Some of these cytokines include IL-1, IL-18, TNFα and IL-12(Dinarello 2000). Specific immunity cytokines are those that can regulate adaptive immune responses (Humoral Immunity and Cell-Mediated Immunity) when they encounter a specific antigen in the cell. These cytokines such as IL2 IL4 IL5 are produced by T-Lymphocytes, mast cells, Th2cells and functions in proliferation and differentiation of B and T-Lymphocytes after antigen recognition and activation of effector cells. IL-2 is secreted by T-cell and helps in T-cell proliferation, NK cell activation and proliferation and B-cell proliferation(DÂ’Souza, Schluns et al. 2002)
Fig 1: Interaction of antigen with macrophages and the subsequent activation of resting TH cells leads to release of numerous cytokines (blue arrows), generating a complex network of interacting cells in the immune response.
PROINFLAMMATORY CYTOKINE- IL-18
Interleukin-18 (IL18) a proinflammatory cytokine is produced by macrophage and other cells that belong to the IL-1 superfamily. Inflammation is the site where there are many cellular interactions between specific tissue cells and infiltering of immune system cells. IL-18 is involved in inflammation by inducing endothelial adhesion molecules, activating the neutrophil to degranulate and stimulates a cascade of gene expression such as proinflammatory type 11 phospholipase(PL)A2, cyclooxygenase (COX)-2, inducible NO synthase and chemokine genes. Gene encoding IL-18 is located on chromosome 11 in humans. IL-18 is structurally similar to IL-1 family with 23-KDa and is in the form of inactive precursor which gets activated when its peptide is cleaved by caspase-1 enzyme. The pro- IL-18 (Inactive form) is expressed in dentritic cells, macrophages, kupffer cells, chondrocytes, keratinocytes, synovial fibroblasts and osteoblaasts. The factor which converts the pro-IL-18 to active form is still not clearly understood but it is proven that increased IL-18 is seen in a wide number of inflammatory disease and autoimmune disorder such as multiple sclerosis, contact hypersensitivity of the skin, psoriasis, chronic inflammatory bowel diseases, human muscular sarcoidosis and in cancer and tumour cells. IL-18 differentiates and activates different T helper (Th) cell subsets depending on their surrounding cytokine profile. If IL-12 is present Th1 response is favoured (e.g. in chronic eczema or psoriatic skin inflammation), in its absence a Th2 response may be enhanced as seen in cutaneous T cell lymphoma associated skin inflammation or acute eczema. Therefore IL-18 bridges the innate and adaptive immune response by its activation of inflammasome(Wittmann, Macdonald et al. 2009). IL-18 amplifies the innate response by inducing the expression of other cytokines such as TNF-α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokines such as IL-8 by peripheral blood mononuclear cells. These cytokines and chemokines in turn up regulate granule formation and thereby lead to inflammation. IL-18 along with its pathological infection consequences has an interesting property of inducing IFNáµ§ along with IL-12 which makes it distinct from the IL-1 family and therefore is a member of the T-cell helper type 1 (Th1)- inducing family of cytokines (IFNáµ§, IL-2, IL-q12, IL-15). It also produces other immunostimulatory cytokines which assist in specific B and T cell mediated response. IL-18 has a wide range of effector functions on invasion of pathogens which makes it an good regulator of innate and acquired immunity. These have been implicated in many chronic disorders. Studies have been done to find out the role of IL-18 with Keratinocytes in the chronic inflammatory skin disease. ((Wittmann, Purwar et al. 2005). IL-18 also has a role to play in Atropy as both IL-18 gene and atopy is mapped to chromosome 11q22. IL-18 enhances IL-4/IL-13 production which induces IgE which is associated with Atropy disorder.(Kruse, Kuehr et al. 2003). IL-18 plays a role in pathophysiology inflammation in Rheumatoid Arthritis (RA) by inducing expression of the vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 on endothelial cells and RA synovial fibrobast (Dai, Matsuno et al. 2004). As IL-18 is seen in the regions of chronic inflammation and IL-18R expression in myeloid cells such as macrophage and Dentritic cells (DC), DC can be made a new target for IL-18. A Novel mechanism can be used where IL-18 is used to recruit DC to areas of inflammation under TH1 cytokine condition where IFN-γ is increased such as psoriasis or inflammatory bowel diseases.
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Different strategies are in clinical trials to inhibit the biological effects of cytokines in immune-mediated inflammatory diseases some of which include monoclonal antibodies against cytokines or their receptors, soluble receptors, receptor antagonists, inhibitors of cytokines processing, cytokine-induced intracellular signals and Vaccination against cytokines has been contemplated as a possible strategy to generate autologous neutralizing antibodies against pro-inflammatory cytokines(Arend, Palmer et al. 2008).
SPECIFIC IMMUNITY CYTOKINE IL-2
Interleukin-2 (IL-2) is a type of cytokine involved in immune system signalling when the body is infected with microbs. It also plays a role in distinguishing the foreign and the self microbs. Antigen which binds to the T cell receptor (TCR) stimulates the secretion of IL-2 and the expression of IL-2 receptors (IL-2R) which is mainly produced by T4-lymphocytes and a minimum amount by T8-Lymphocytes. The expressed IL-2 acts like a growth factor for NK cells and antigen-stimulated T-lymphocytes and B-lymphocytes. IL-2 increases the killing ability of NK cells, increases the synthesis of other cytokines, increases Fas-mediated apoptosis and stimulates antibody synthesis by B-lymphocytes. The role of IL-2 in regulation of CD8 T cell remains enigmatic but studies demonstrate that the expansion of CD8 T cell in secondary lymphoid is IL-2 independent but IL-2 is required for continuous expansion of the CD8 T cells in the non-lymphoid tissue (DÂ’Souza, Schluns et al. 2002). IL-2 also promotes the function of CD8+ T cells. The antigen-induced expression of Eomesodermin (Eomes), maturation of naive CD8+ T cells into granzyme B- and CD44-expressing effector CD8+ T cells is enhanced by IL-2. CD8+ T cells activated with IL-2 can lyse tumor targets, which has led to use of IL-2 for the generation of T cells and for cell transfer therapies for cancer patients (Hinrichs, Spolski et al. 2008). The goal of vaccination is to provide a long term protective immunity to body by producing CD8+ memory T cells. Expression of IL-7R is an important property of memory T cells whose sustained expression is promoted by IL-2. Therefore, IL-2 signals are required during priming to induce reexpression of IL-7α on late activated T cells(Dooms, Wolslegel et al. 2007). IL-2 plays a pivotal role in controlling the survival and proliferation of regulatory T (Treg) cells which is required for the maintenance of immune tolerance. Moreover, IL-2 is also involved in the homeostasis and differentiation of effector T-cell subsets, which includes TH1, TH2 and TH17. Figure 2 shows the effect of IL-2 on T-cell subsets. IL-2 receptor is composed of three distinct subunits which are important for the delivery of IL-2 signal to Treg, these include α (CD25), β (CD122), and γ (γc) chains. Of these expression of CD25 is crucial as it confers high affinity binding to IL-2 along with CD122 and γc(Létourneau, Krieg et al. 2009)
Figure 2: Effect of IL-2 on T-cell subsets. When IL-2 binds to its receptor it triggers the upregulation or downregulationof transcription factors (adepicted in dark green ovals), cytokine receptors(depicted on the left side of the T cell), or effector functions( depicted on the right side of the T cell)
IL-2 promotes proliferation, differentiation, and function of activated CD41 and CD81 T cells but in contrary also induces activation-induced cell death of CD41 T cells and mediates the survival of Treg cells. Therefore, evidence suggests that the key role for IL-2 is maintaining the balance between protection from pathogens and suppression of self-reactive T cells by providing a powerful negative feedback loop to immune responses. NK cells (CD56bright) which are present in human lymph nodes express high-affinity interleukin IL-2 receptor and produces immunoregulatory cytokines. T cell derived IL-2 with NK IL-2R costimulates CD56bright NK cells to produce IFN-gamma . (Fehniger, Cooper et al. 2003)
Adaptive immunoregulators plays a role in innate cytokine production, which in turn influence the developing antigen-specific immune response Further investigation of IL-2 regulation will lead to a better understanding of the complex mechanisms underlying the adaptive immunity.