title: Protein Kinase R Mediates the Inflammatory Response Induced by Hyperosmotic Stress.
abstract: High extracellular osmolarity results in a switch from an adaptive to an inflammatory gene expression program. We show that hyperosmotic stress activates the protein kinase R (PKR) independently of its RNA-binding domain. In turn, PKR stimulates nuclear accumulation of nuclear factor κB (NF-κB) p65 species phosphorylated at serine-536, which is paralleled by the induction of a subset of inflammatory NF-κB p65-responsive genes, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and IL-1β. The PKR-mediated hyperinduction of iNOS decreases cell survival in mouse embryonic fibroblasts via mechanisms involving nitric oxide (NO) synthesis and posttranslational modification of proteins. Moreover, we demonstrate that the PKR inhibitor C16 ameliorates both iNOS amplification and disease-induced phenotypic breakdown of the intestinal epithelial barrier caused by an increase in extracellular osmolarity induced by dextran sodium sulfate (DSS) in vivo Collectively, these findings indicate that PKR activation is an essential part of the molecular switch from adaptation to inflammation in response to hyperosmotic stress.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Farabaugh
authors.affiliation: Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Mithu
authors.initials: M
authors.lastname: Majumder
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Jobava
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xing-Huang
authors.initials: XH
authors.lastname: Gao
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Schuster
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Longworth
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.affiliation: Department of Clinical and Experimental Medicine, Universita degli Studi di Parma, Parma PR, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Dey
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA pxr150@case.edu mxh8@case.edu.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramakrishnan
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA pxr150@case.edu mxh8@case.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism; D004789:Enzyme Activation; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015538:Nitrosation; D009997:Osmotic Pressure; D010641:Phenotype; D010766:Phosphorylation; D012330:RNA, Double-Stranded / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019892:eIF-2 Kinase
keywords: DSS; PKR; hyperosmotic stress; iNOS