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Interferon is one of the cytokines that links the innate and adaptive immunity in vertebrate. It is particularly important in defense against intracellular pathogens. IFN-γ is produced by lymphocytes, natural killer cells as well as monocytes (4). It enhances the microbicidal activities of macrophages and neutrophils by increasing receptor-mediated phagocytosis, inducing respiratory burst, and initiating nitric oxide production (4). INF-γ also upregulates expression of class I MHC, thereby, increasing the likelihood of cytotoxic T-cell to recognize invading pathogens (4). IFN-γ also upregulates the MHC class II antigen presentation pathway and corresponding CD4+ T-cell activation.
Interleukin-1 is a pro-inflammatory cytokine, which plays critical role in the host defense against infections. IL-1 activates endothelial cells and leukocytes, as well as acute phase protein synthesis in response to invasion by pathogens (5). IL-1 also induces production of other cytokines such as IL-8, TNF-α, IL-6, and IL-12. Further, it enhances the effects of TNF-α and IL-6. Variety of cells, including macrophages, monocytes, lymphocytes, dendritic cells, endothelial and epithelial cells produce IL-1 (6). Expression of IL-1 is induced in response to bacterial, viral, fungal, and parasitic infections, as well as by other cytokines such as TNF-α, IL-12. IL-1 production is also upregualeted by IL-1 itself. Complement component 5a also activates cells to produce IL-1 (7).
Interleukin-1 is expressed as either IL-1α or IL-1β. IL-1α generally remains inside the cell and mediates local inflammation, whereas IL-1β is generally secreted, which mediates both local and systemic inflammatory responses (5).
Interleukin-6 is a pleiotropic cytokine, which has both pro- and anti-inflammatory properties. This cytokine is produced by a number of cells, including lymphocytes, monocytes, macrophages, neutrophils, endothelial cells and fibroblasts. Production of interleukin-6 is induced by bacteria, viruses as well as other cytokines, such as TNF-α and IL-1β (8). Interleukin-6 is involved in B-cell differentiation and antibody production, as well as T-cell activation. It also increases pro-inflammatory responses of neutrophils (8). The anti-inflammatory activity of IL-6 is exerted by inhibition of IL-1β and TNF-α expression, as well as stimulation of expression of IL-1-receptor antagonist and soluble TNF receptor. IL-6 also induces synthesis of acute phase proteins in the liver. Acute phase proteins participate in elimination of pathogens from the host and downregulation of the inflammatory response (9).
Interleukin-8 is chemotactic cytokine or chemokine, which preferentially recruits neutrophils to infected tissues. It also activates and increases respiratory burst activity and degranulation of neutrophils. IL-8 also attracts T lymphocytes to the site of inflammation by a lesser extent (10). Being resistant to proteolytic degradation, IL-8 can exert its effects for a long time compared to other cytokines. IL-8 is produced by monocytes, endothelial and epithelial cells, fibroblasts, neutrophils and T-lymphocytes (11). Production of IL-8 is induced by exogenous stimuli such as bacteria, viruses, fungi, parasites, as well as by products derived from these pathogens. Cytokines such as TNF-α and IL-1β also induce production of IL-8 (11).
Interleukin-10 is an anti-inflammatory cytokine, which is mainly produced by monocytes. T cells, B cells and mast cells also produce IL-10 by some extent. IL-10 inhibits production of pro-inflammatory cytokines by neutrophils, monocytes and macrophages (12). It also increases production of IL-1 receptor antagonist and soluble TNF receptors, thereby, restricting cytokines IL-1 and TNF-¡ from exerting their pro-inflammatory effects. IL-10 also downregulates expression of MHC class II, thereby, impairing the ability of monocytes and macrophages to present antigen to T cells. While IL-10 increases B cell function, it suppresses the production of IFN-γ and IL-12, which are involved in promoting T cell response (12).
IL-12 is produced mostly by dendritic cells and monocytes. Neutrophils also produce IL-12 by a lesser extent. Production of IL-12 is induced by bacteria, parasites, viruses as well as fungi. IFN- can also induce production of IL-12 by macrophages. IL-12 is affective against both extracellular and intracellular pathogens (13). The cytokine helps in activation of macrophages by inducing production of IFN- by T lymphocytes (14). It also increases production of TNF-α, IL-8, and IL-10 (15). IL-12 enhances the cytotoxic activity of cytotoxic T cells and natural killer cells (16).
Transforming Growth Factor-α
Transforming growth factor (TGF)-α is a pro-inflammatory cytokine. It upregulates IL-8 (17) and PGE2 production (18) as well as enhances the effects of TNF-α and IL-1β (17). TGF-¡ also induces breakdown of the endothelial-epithelial barrier function, resulting in edema formation (19). TGF-α is produced by many cells including epithelial cells, fibroblasts, neutrophils, macrophages, and eosinophils (20).
TGF-β plays important role in cell growth and differentiation. It also works as a suppressor of immune and inflammatory responses. The immunoregulatory effects of TGF-β include
inhibiting macrophage cytokine and nitric oxide production and respiratory burst activity;
limiting IFN-γ production;
increasing IL-1 receptor antagonist expression; and
enhancing macrophage clearance of injured parenchymal cells, inflammatory cells and bacterial debris.
Transforming growth factor-β is expressed by a variety of leukocytes as well as other cell types, including epithelial cells (21).
Tumor necrosis factor (TNF)-α is a highly pro-inflammatory cytokine with both beneficial and injurious properties (22). At the local level, TNF-α promotes endothelial activation and the recruitment of leukocytes to the site of infection (23). The systemic effects of TNF-α include induction of fever and acute phase protein synthesis. Although these local and systemic effects are beneficial to the host innate immune defense against infection, TNF-α can cause hyper activation of the immune system leading to inflammatory responses that can be life threating for the host. It has been shown to induce shock, tissue injury, vascular leakage, multiple organ failure and dysregulated coagulopathy (22). TNF-α is able to exert its effects directly or indirectly by stimulating the production of secondary mediators. It is produced by macrophages, lymphocytes, neutrophils and epithelial cells (24). Inducers of TNF-α production include viral, fungal and parasitic pathogens, bacterial wall products, toxins as well as other cytokines such as IL-1 and IFN-γ, and complement components.