Down-regulators of TNF

Biologic agents targeting specific sites in the immunoinflam-matory cascade are being used to treat Crohn s disease. TNF a antibody therapies such as infliximab, are a standard therapy for severe Crohn s disease, Thahdomide whose effect is partially mediated by down regulation of TNF a has efficacy in previously refractory Crohn s patients (Ginsberg et al., 2001). 

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. 

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. 

Tsuboi 1, Tanaka H, Nakao M, et al. Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes up-regulation of TNF, IFN-y and IL-2, in contrast to down-regulation of IL-6 production. Cytokine 1995 7 372-9. 

Of the various factors suggested to play a part in impaired adipocyte function in insuhn resistance and NIDDM, increased TNF-a expression and production have attracted interest. TNF-a is produced and secreted from adipose tissue in obesity and thus acts in an autocrine fashion to alter adipocyte function during obesity-hnked insuhn resistance [385-387]. Long-term exposure (>6h) to TNF-a has been shown to stimulate hpolysis in adipocytes [368, 388], despite inducing reduced HSL expression [389, 390]. An early study showed a down-regulation of HSL gene expression upon TNF-a treatment of 3T3-L1 cells, as measured by Northern blot analysis and enzyme activity measurements [391]. A similar effect, although much more moderate, was seen more recenfly at the protein level [264]. In a study wifh primary rat adipocytes, however, no alteration of the levels of HSL protein occurred upon treatment wifh TNF-a [392]. 

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