Cytokine, proinflammatory

In type III or immunocomplex-mediated allergy, IgG antibodies form complexes with antigen. At low exposures, the body is able to remove diese complexes, but if there is a severe exposure, immunocomplexes release a variety of proinflammatory cytokines. The involvement of this mechanism is clearest in serum sickness. This mechanism is also considered to be most important in the development of extrinsic allergic alveolitis (hypersensitivity pneumonitis, especially... 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

In summary, recent years have seen the emergence of encouraging data for antibodies in clinical development that are directed against proinflammatory cytokines, inflammatory cells or co-stimulatory molecules. In particular, anti-TNFa therapies have set a new standard for symptom control and prevention of joint destruction in RA. 

The key end result of TLR signalling is the induction of cytokines. Cytokines are proteins produced during an immune response that allow the maturation, activation and differentiation of effector cells in the immune system. The activation of NFkB and AP-1 by the MyD88 and the TREF dependent pathways leads to the production of proinflammatory cytokines such as IL-6, TNF-a and various chemokines. This pathway can also activate IRF-7 via TLR-7and TLR-9 allowing Type-I interferons to be produced. 

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Gene regulation by tocopherols has mainly been associated with PKC because of its deactivation by a-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, API). A direct participation of the pregnane X receptor (PXR)/ retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element appear in some cases to be implicated as well. The obser ved immunmodulatory function of a-tocopherol may also be attributed to the fact that the release of the proinflammatory cytokine interlukin-l 3 can be inhibited by a-tocopherol via... 

NF-kB Activators Proinflammatory cytokines Bacterial and viral infection Reactive oxygen species... 

MUligan ED, O Connor KA et al (2001) Intrathecal HlV-1 envelope glycoprotein gpl20 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosd 21(8) 2808-2819... 

Wetzel MA, Steele AD, Eisenstein TK, Adler MW, Henderson EE, Rogers TJ (2000) Mu-opioid induction of monocyte chemoattractant protein-1, RANTES, and IFN-gamma-inducible protein-10 expression in human peripheral blood mononuclear cells. J Immunol 165 6519-6524 Widmer U, Manogue KR, Cerami A, Sherry B (1993) Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol 150 4996-5012 Ye RD (2001) Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. [Review] [136 refs]. J Leukoc Biol 70 839-848... 

Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J (2004) A role for proinflammatory cytokines and fractaUdne in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33) 7353-7365 Kim YS, Panganiban AT (1993) The full-length tat protein is required for TAR-independent, post-transcriptional trans activation of human immunodeficiency virus type 1 env gene expression. J Virol 67(7) 3739-3747... 

Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, Baker EM, Jekich BM, Wieseler JL, Somogyi AA, Martin D, Poole S, Judd CM, Maier SF, Watkins LR (2008) Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun 22 1178-1189... 

Parodi, RE. et al.. Oral administration of diferuloylmethane (curcumin) suppresses proinflammatory cytokines and destructive connective tissue remodeling in experimental abdominal aortic aneurysms, Ann. Vase. Surg., 20, 360, 2006. 

Jung, H. W. Chung, Y. S. Kim, Y. S. Park, Y.-K. Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kB in LPS-stimulated BV-2 microglial cells. Exp. Mol. Med. 2007, 39, 715-721. 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

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