ABSTRACT
Tumor necrosis factor-alpha (TNF-a) is a proinflammatory cytokine produced mainly by monocytes/macrophages but also by B cells, T cells, and fibroblasts. TNF-a production can be stimulated by interferon-gamma (IFN-y) and lipopolysaccharide (LPS). The latter is a component of gram-negative bacterial cell wall and hence TNF-a has been implicated in the pathogenesis of endotoxic shock syndrome (l). TNF-a is a 17-k.Da protein composed of three subunits and it binds to TNF receptors (TNFR) on the surface of cell membranes. TNFR has two types: p55 and p75. Each contains four cysteine-rich repeats in its extracellular domain, a transmembrane domain, which is susceptible to proteinase lysis, and a cytoplasmic tail capable of signal transduction. The intracellular domains of p55 and p75 TNFR do not share any significant homology, which suggests they have different mechanisms of signal transduction pathways. Hence, blockage of binding of TNF-a to both p55 and p75 TNFR is essential to abolish its effects completely. Soluble forms of both TNFR are found and are thought to function as naturally occurring inhibitors of TNF-a.
