title: Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase expression by endoplasmic reticulum stress.
abstract: Endoplasmic reticulum (ER) stress is induced in infectious and inflammatory conditions, but its role in inflammatory responses still remains elusive. In this study we found tunicamycin (TM) and brefeldin A (BFA), two ER stressors, could attenuate lipopolysaccharide (LPS)-elicited inducible nitric oxide synthase (iNOS) gene expression in murine RAW264.7 macrophages, and this effect was not resulting from the effects on IKK or MAPKs activation. However, ER stressors could block NF-κB binding to the iNOS promoter in late-phase signaling evoked by LPS. Results indicated that inhibition of RelB nuclear translocation and p300 expression are involved in the anti-inflammatory actions of ER stressors. We also found that ER stressors could block LPS- and IFN (α, β, and γ)-mediated STAT1 phosphorylation. Our results suggest that activation of MKP-1 via a Ca/calmodulin/calcineurin pathway accounts for the inhibitory effect of ER stressors on IFN signaling. MKP-1 was downregulated by IFN-γ and is a newly identified protein phosphatase targeting STAT1. Taken together, these results indicate that multiple mechanisms are involved in the inhibition of LPS-induced iNOS gene expression by ER stressors. These include downregulation of RelB and p300, upregulation of MKP-1, and inhibition of the JAK/STAT signaling pathway.
authors: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hui-Ju
authors: HJ
authors: Ho
authors: Duen-Yi
authors: DY
authors: Huang
authors: Feng-Ming
authors: FM
authors: Ho
authors: Long-Teng
authors: LT
authors: Lee
authors: Wan-Wan
authors: WW
authors: Lin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051841:Transcription Factor RelB / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C497594:Relb protein, mouse; D050794:STAT1 Transcription Factor; D014415:Tunicamycin; D051841:Transcription Factor RelB; D020126:Brefeldin A; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D050880:p300-CBP Transcription Factors; D053612:Janus Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse