title: Pifithrin-α, a pharmacological inhibitor of p53, downregulates lipopolysaccharide-induced nitric oxide production via impairment of the MyD88-independent pathway.
abstract: The effect of pifithrin (PFT)-α, a pharmacological inhibitor of p53, on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. PFT-α inhibited the production of NO but not tumor necrosis factor (TNF)-α in response to LPS. PFT-α inhibited LPS-induced NO production via reduced expression of an inducible NO synthase (iNOS). Moreover, PFT-α inhibited LPS-induced iNOS expression in p53-silenced cells. PFT-α inhibited the production of interferon (IFN)-β, characteristic of the MyD88-independent pathway of LPS signaling, whereas it did not affect the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. PFT-α inhibited poly I:C-induced NO production whereas it did not inhibit IFN-β-induced NO production. Further, PFT-α reduced the expression of IFN regulatory factor 3 that leads to the IFN-β production in the MyD88-independent pathway. The most upstream event impaired by PFT-α was the reduced expression of TNF receptor-associated factor (TRAF) 3 in the MyD88-independent pathway. PFT-α also reduced the in vivo expression of iNOS in the livers of mice injected with LPS. Taken together, PFT-α was suggested to inhibit LPS-induced NO production via impairment of the MyD88-independent pathway and attenuated LPS-mediated inflammatory response.
authors: Department of Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors: Adilsaikhan
authors: A
authors: Mendjargal
authors: Erdenezaya
authors: E
authors: Odkhuu
authors: Naoki
authors: N
authors: Koide
authors: Hiroshi
authors: H
authors: Nagata
authors: Tsuyoshi
authors: T
authors: Kurokawa
authors: Toshiaki
authors: T
authors: Nonami
authors: Takashi
authors: T
authors: Yokochi
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control; D020868:Gene Silencing; D016899:Interferon-beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C482199:lipopolysaccharide, E coli O55-B5; D009569:Nitric Oxide; D014050:Toluene; D016899:Interferon-beta; C121565:pifithrin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse