Attenuation of tumor necrosis factor alpha gene transcription in macrophages by an autocrine factor.

Abstract

Bacterial cell products such as lipopolysaccharide(LPS) trigger the innate immune response to gram-negative bacterial pathogens. LPS, or endotoxin, is a potentactivator of monocytes/macrophages and elicits the production of antimicrobial products (e.g., nitric oxide) andpro-inflammatory cytokines such as interleukin-1 (IL-1)and tumor necrosis factor α (TNFα). A controlled response to endotoxin results in elimination of the bacterialpathogen without undue adverse effects on the host.However, repeated or massive exposure to LPS maycause acute inflammation or, more seriously, septicshock. Septic shock is a critical, often lethal, condition resulting from increased vascular permeability and loss ofblood pressure as well as multiple organ failure. It hasbeen well documented that the effects of endotoxin aremediated by pro-inflammatory cytokines, in particularTNFα (Tracey and Cerami 1994). Indeed, many of thepathogenic effects of LPS are mimicked by administration of TNFα. Conversely, lethality caused by injectingLPS into mice can be mitigated by prior administration ofa neutralizing TNFα antibody (Beutler et al. 1985)...