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Th1 and Pro-inflammatory Cytokines See also factors affecting Th1/Th2 development See also cytokines secreted during Th development See also Proinflammatory Signalling Proinflammatory cytokines stimulate transcription of several genes involved in the inflammatory and immune response through coordinate induction of multiple signling pathways, including MAPKs as well as IkB kinase (IKK). IKK phosphorylates and targets the IkBs for proteasomal degradation. Chronic inflammatory diseases such as rheumatoid arthritis are characterized by an accumulation of immune cells, such as phagocytic lymphoctes and macrophages at the stie of the injury. The proliferation, differentiation, and activation of these cells are controlled by cytokines. Among the cytokines, the proinflammatory cytokines IL-1, IL-6 and TNF-alpha play a key role. These proinflammatory cytokines not only activate the cells of the immune system but also stimulate the cells of affected organism. In this way, they enhance their own synthesis and that of other inflammatory mediators such as prostaglandins, reactive oxygen species (ROS) and nitric oxide (NO). What induces Pro-inflammatory Cytokines? The primary initiating stimuli of inflammation signal through either of two major classes of cell surface receptor: the Toll (See Toll Like Receptors) and interleukin-1 (IL-1) receptor (TIR) family and the tumour necrosis factor (TNF) receptor family. These are unrelated, but both types activate a common set of four well characterized intracellular signalling pathways. These are the protein kinase system that leads to the activation of the transcriptional regulator nuclear factor kB (NFkB), and the three mitogen activated protein kinase (MAPK) cascades. At the bottom of the cascades are the proteins that regulate expression of the inflammatory response genes. Many of these reponse genes act on transcription, but some act post-transcriptionally, particularly in the control of mRNA stability. Many of the proteins of the inflammatory response have potent effects and need to be tightly controled. Thus a common theme ais complex regulatory mechanisms that permit rapid and substantial changes in expression. Viruses: Viral infections induce expression of several inflammatory cytokines and chemokines that can participate in immune responses. Multiple intracellular pathways including protein kinase R (PKR), IFN regulatory factors, p38 mitogen activated protein kinase (MAPK), and NF-kB are necessary for viral induction of inflammatory cytokines. Pro-inflammatory Cytokines The major pro-inflammatory cytokines are IL-12, TNFα and IFN-γ. TNF is among the early activated cytokines in inflammation together with IL-1, IFNy and IL-6. IL12 (click here for more information) Il-12 is required for Th1-cell differentation. IFN-γ (click here for more information) IL-1: IL-8: plays a pivotal role in recruitment and activation of neutrophils and monocytes in various experimental models of acue inflammation. See Chemokines for more information on IL-8 IL-17: has been identified as a cellular ortholog of a protein encoded by the T lymphotropic Herpes virus Slmiri (HSV). It a potent pro-inflammatory cytokine associated with autoimmune inflammatory disease. IL-17 cooperates with TNFalpha to stablize KC mRNA. Il017 is a homodimeric cytokine of about 32 kDa which is synthesized and secreted only by CD4+ activated memory T cells. Despirte its restricted tissue distribution, IL_17 exhibits peitropic biological activites on various types of cells. It has been found to simulate the production of m any cytokines. It induces the secretion of IL-6, IL08, IL_12, leukemia inhibitory factor (LIF), prostaglandin E2, MCP-1 and G-CSF by adherent cells like fibroblasts, keratincotyes, epithelial and endothelial cells. It also has the ability to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of DC34+ human progenitors into neutrophils. It has also been implicated in bone metabloism, and has been suggested to play an important role in pathological conditions characterized by the presence of activated T cells and TNF--alphaproduction such as rheumatoid arthritic and loosening of bone implants. Consistent with its wide-range of effects, the cell surface receptor for IL-17 has been found to be widely expressed in many tissues and cells types. Related proteins to IL-17 have been identified. (see, for example, IL-17B and IL-17C US Patent Application Publication 2003/0003546A1). IL-18 has a synergistic effect with IL-12 in the production of IFN-y. IL-18 is important in host defense against infection. Exogenous administration of IL-18 promoted clearance of microorganissms such as C. neoformans, Candida albicans, Toxoplasma gondii and herpes simplex virus from infected tissues. IL-27: is a novel IL-6/IL12 family that is considered to play a role in Th1 differentiation. It is a heterodimeric cytokine that consists of an IL-12 p40 related protein, EBV-induced gene 3, and a newly discovered IL-12 p35 related protein p28. GM-CSF Lymphotoxin: Suppression of Inflammation: Glucocorticoids: suppresses many genes of the inflammatory response which may be due in part to actions on the intracellular signalling pathways used by inflammatory stimuli. Synthetic glucocorticoids are used widely for anti-inflammatory therapy in diseases such as rheumatoid arthritics, Crohn's disease and asthma, and as immunosuppressants in transplantation. Although very potent in suppressing inflammation, they have a variety of side effects including osteoporosis, diabetes, cataracts, hypertension. Physiologically, glucocorticoids are produced in increased amounts in response to physical stress such as infection. Glucocorticoids also have post transcriptional effects on the expression of genes of the inflammatory response: they destabilize the mRNAs of COX-2 and several cytokines. This is likely to be because they prevent the p38 MAPK mediated stabilization of mRNAs. |
