title: Interferon regulatory factor-1 regulates the autophagic response in LPS-stimulated macrophages through nitric oxide.
abstract: The pathogenesis of sepsis is complex and, unfortunately, poorly understood. The cellular process of autophagy is believed to play a protective role in sepsis; however, the mechanisms responsible for its regulation in this setting are ill defined. In the present study, interferon regulatory factor 1 (IRF-1) was found to regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS-stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore, we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation in which IRF-1/NO inhibits autophagy through mTOR activation.
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Lemeng
authors: L
authors: Zhang
authors: Jon S
authors: JS
authors: Cardinal
authors: Runalia
authors: R
authors: Bahar
authors: John
authors: J
authors: Evankovich
authors: Hai
authors: H
authors: Huang
authors: Gary
authors: G
authors: Nace
authors: Timothy R
authors: TR
authors: Billiar
authors: Matthew R
authors: MR
authors: Rosengart
authors: Pinhua
authors: P
authors: Pan
authors: Allan
authors: A
authors: Tsung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D019446:Endotoxemia / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D009569:Nitric Oxide