Inhibition of IL-12 production in human monocyte-derived macrophages by TNF

IL-12 is a pivotal cytokine that links the innate and adaptive immune respo nses. TNF-alpha also plays a key role in orchestrating inflammation and imm unity. The reciprocal influence of these two inflammatory mediators on each other may have significant impact on the cytokine balance that shapes the type and extent of immune responses. To investigate the relationship betwee n TNF-alpha and IL-12 production, we analyzed the effects of exposure of hu man monocyte-derived macrophages to TNF-alpha on LPS- or Staphylococcus aur eus-induced IL-12 production in the presence or absence of IFN-gamma, TNF-a lpha is a potent inhibitor of IL-12 p40 and p70 secretion from human macrop hages induced by LPS or S. aureus, IL-10 is not responsible for the TNF-alp ha-mediated inhibition of IL-12. TNF-alpha selectively inhibits IL-12 p40 s teady-state mRNA, but not those of IL-12 p35, IL-1 alpha, IL-1 beta, or IL- 6. Nuclear run-on analysis identified this specific inhibitory effect at th e transcriptional level for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major transcriptional factors identified to be involved in th e regulation of IL-12 p40 gene expression by LPS and IFN-gamma, i.e., c-Rel , NF-kappa B p50 and p65, IFN regulatory factor-1, and ets-2, were not affe cted by TNF-alpha when examined by nuclear translocation and DNA binding. T hese data demonstrate a selective negative regulation on IL-12 by TNF-alpha , identifying a direct negative feedback mechanism for inflammation-induced suppression of IL-12 gene expression.