A role for Stat1 in the regulation of lipopolysaccharide-induced interleukin-1beta expression.
Because the induction of interleukin-1beta (IL-1beta) 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-1beta 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-1beta 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-1beta 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-1beta mRNA was expressed in these mice but not in macrophages from MyD88(/) mice. Despite the presence of IL-1beta mRNA, IL-1beta 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-1beta requires both the MyD88-dependent induction of IL-1beta mRNA and pro-IL-1beta as well as the MyD88-independent, Stat1-mediated processing of that gene product into active cytokine.
Joshi
Vishwas D
VD
Department of Medicine, Division of Geographic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Kalvakolanu
Dhananjaya V
DV
Chen
Wilbur
W
Zhang
Lei
L
Kang
Tae Jin
TJ
Thomas
Karen E
KE
Vogel
Stefanie N
SN
Cross
Alan S
AS
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D016898:Interferon-alpha / Q000037:antagonists & inhibitors; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000502:physiology*
D016898:Interferon-alpha; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016899:Interferon-beta; D007371:Interferon-gamma