Down-regulators TNF

The effect of IFN-y on TNF-Rs is complex. While IFN-y induces cells to synthesize TNF and IL-1 and thus could down-regulate TNF-Rs, IFN-y actually increases the number of surface TNF-Rs without a significant change in binding affinity (Aggarwal et al., 1985 Tsujimoto and Vilcek, 1987). This effect of IFN-y is similar for both receptor types in many myeloid and epithelial cells (Pandita et al., 1992). However, in mouse peritoneal M<(),... 

Tikhonov I, Doroshenko T, Chaly Y, Smolnikova V, Pauza CD, Voitenok N. Down-regulation of CXCR1 and CXCR2 expression on human neutrophils upon activation of whole blood by S. aureus is mediated by TNF-a. Clin Exp Immunol 2001 125 414-422. 

TNF is produced and secreted by activated cells within minutes following contact with LPS, reaching peak levels at 90-120 minutes after the admnistration of Escherichia coli endotoxin in human volunteers (M27). Van Deventer et al. (D15) could not detect serum TNF levels during experimental endotoxemia. Even during continuous intravenous administration of recombinant TNF (rTNF), serum TNF rapidly becomes undetectable (M27). It has been proposed that circulating soluble TNF receptors (sTNF-Rs) may be an important down-regulating mechanism (G10). 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

Adalimumab is a fully human IgGi anti-TNF monoclonal antibody. This compound complexes with soluble TNF-ct and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T cell function. 

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