A role for Stat1 in the regulation of lipopolysaccharide-induced interleukin-1β expression

Because the induction of interleukin-1 beta (IL-1 beta) is critical to antibacterial host defenses and its excessive generation is a prominent component of sepsis, regulation of this proinflammatory cytokine is a critical factor in the immune response to lipopolysaccharide (LPS). We previously showed that LPS-induced IL-1 beta expression was regulated by a Stat1-dependent, nitric oxide (NO)-mediated mechanism. Subsequent in vivo studies showed that whereas Stat1 had a role in the downregulation of IL-1 beta expression, it had a more significant effect on its initial induction. Although both interferon-beta (IFN-beta) and IFN-gamma activate Stat1, the early appearance of IFN-beta in the circulation after LPS administration suggested its pivotal role in Stat1-mediated IL-1 beta expression in vivo. Further in vitro analysis of peritoneal macrophages from IFN-beta(-/-), Stat1(-/-), and caspase-1(-/-) mice and their wild-type controls following LPS stimulation demonstrated that IL-1 beta mRNA was expressed in these mice but not in macrophages from MyD88(-/-) mice. Despite the presence of IL-1 beta mRNA, IL-1 beta protein was markedly reduced in the absence of Stat1 activation in macrophages derived from IFN-beta(-/-) and Stat1(-/-) mice or in the absence of caspase-1 activity, which itself was dependent on Stat1 activation. These studies support the hypothesis that the expression of IL-1 beta requires both the MyD88-dependent induction of IL-1 beta mRNA and pro-IL-1 beta as well as the MyD88-independent, Stat1-mediated processing of that gene product into active cytokine.