DECREASED IL-12 PRODUCTION AND TH1 CELL-DEVELOPMENT BY ACETYL SALICYLIC ACID-MEDIATED INHIBITION OF NF-KAPPA-B

IL-12 is a 75-kDa heterodimeric cytokine composed of two covalently li nked p35 and p40 chains. This pro-inflammatory cytokine plays a promin ent role in the development of Th1 cell-mediated immune responses. Th1 cell-mediated immune responses have been implicated in the pathogenes is of chronic inflammatory autoimmune diseases. Thus, IL-12 appears to be a critical factor in the generation and mainteinance of chronic in flammatory conditions. In this study, we investigated the effects of a commonly prescribed antiinflammatory drug, acetyl salicylic acid (ASA ), on IL-12 production and Th1 cell development. ASA was found to inhi bit secretion of the IL-12 heterodimer as well as p40 monomer by human monocytic cells. This was associated with the down-regulation of IL-1 2p40 mRNA expression. Analysis of the regulation of the p40 gene promo ter revealed that ASA inhibited NF-kappa B activation and binding to t he p40-kappa B site in the p40 promoter, leading to transcriptional re pression of the p40 gene. Addition of ASA to an in vitro T helper cell differentiation system, at concentrations compatible with plasma leve ls reached during anti-inflammatory therapy, resulted in reduced devel opment of Th1 cells. These results suggest that the inhibition of NF-k appa B activation by ASA leads to down-regulation of IL-12 production and inhibition of Th1 cell development.