IFN-gamma inhibits lipopolysaccharide-induced interleukin-1 beta in primary murine macrophages via a Stat1-dependent pathway.
Interleukin-1 (IL-1) plays an important role in host defenses against microbial pathogens. Excessive production of this cytokine, however, may be responsible in part for the lethality observed during sepsis. Our studies show that interferon-gamma (IFN-gamma) downregulates lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta) transcription in primary macrophages. This phenomenon does not occur in splenocytes or bone marrow-derived macrophages from signal transducer and activator of transcription (Stat1)-deficient mice, suggesting that Stat1, a transcription factor involved in IFN signaling, plays a critical role in this process. Moreover, nitric oxide (NO) was also involved in the downregulation of LPS-induced IL-1 by IFN, as addition of the inducible nitric oxide synthase (iNOS) inhibitor L-N(6)-(1-iminoethyl)lysine (NIL) negated the effect. Kinetic analysis of IL-1 and IFN levels in LPS-treated mice in vivo suggests that IFN-mediated inhibition of IL-1 might be an important negative feedback mechanism for limiting IL-1 generation in vivo.
De Boer
M L
ML
Division of Infectious Diseases, Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
Hu
J
J
Kalvakolanu
D V
DV
Hasday
J D
JD
Cross
A S
AS
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D007700:Kinetics; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D007371:Interferon-gamma