POTENT SUPPRESSION OF IL-12 PRODUCTION FROM MONOCYTES AND DENDRITIC CELLS DURING ENDOTOXIN TOLERANCE

Endotoxin tolerance, the down-regulation of a subset of endotoxin-driv en responses after an initial exposure to endotoxin, may provide prote ction from the uncontrolled immunological activation of acute endotoxi c shock. Recent data suggest, however, that the inhibition of monocyte /macrophage function associated with endotoxin tolerance can lead to a n inability to respond appropriately to secondary infections in surviv ors of endotoxic shock. IL-12 production by antigen-presenting cells i s central to the orchestration of both innate and acquired cell-mediat ed immune responses to many pathogens. IL-12 has also been shown to pl ay an important role in pathological responses to endotoxin. We theref ore examined the regulation of IL-12 during endotoxin tolerance. Primi ng doses of lipopolysaccharide ablate the IL-12 productive capacity of primary human monocytes. This suppression of IL-12 production is prim arily transcriptional. Unlike the down-regulation of TNF-alpha under s uch conditions, the mechanism of IL-12 suppression during endotoxin to lerance is not dependent upon IL-10 or transforming growth factor-beta , nor is IL-12 production rescued by IFN-gamma or granulocyte-macropha ge colony-stimulating factor. Of note, human dendritic cells also unde rgo endotoxin tolerance, with potent down-regulation of IL-12 producti on. Endotoxin tolerance-related suppression of IL-12 production provid es a likely mechanism for the anergy seen during the immunological par alysis which follows septic shock.