Tumor necrosis factor-a is a proinflammatory cytokine which plays a key role in most of the inflammatory processes as well as in immune responses to infections and tumor antigens. TNF- is largely produced and released by macrophages and monocytes. It exists as a soluble 17-kDa sized protein made of three subunits. The cytokine stands at the beginning of a cascade of pro-inflammatory cytokines and triggers off pro-inflammatory signals at the target cell by binding to membrane-based TNF receptors, e.g., on T cells and macrophages. Furthermore, TNF- causes a rise in body temperature as well as the induction of the acute phase proteins, an increased migration of dendritic cells from the periphery to regional lymph nodes and an activation of neutrophils. In inflammatory diseases, TNF- possesses pleiotropic effects and leads, among other factors, through the activation of a pro-inflammatory cytokine cascade, to an induction of adhesion molecules on endothelial cells (E-selectin, ICAM-1), which leads to an increased migration of leukocytes. Furthermore, TNF- induces the secretion of metallo-
8.3 Inhibitors of TNF-a in the Treatment of Autoimmune Bullous Skin Disorders
proteinases and the release of pro-inflammatory cytokines (IL-1, IL-6, IL-8, GM-CSF). TNF-a-conveyed induction of pro-inflammatory cytokines, leukocyte chemotaxis and angiogenesis possibly play a fundamental role in autoimmune diseases of the skin, presumably diseases which are characterized by elevated TNF- serum concentrations, fever and an increase of acute phase proteins. Elevated serum levels of TNF-are detectable in many autoimmune diseases including RA, psoriasis and Crohn's disease.
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