title: MKP-1 negatively regulates LPS-mediated IL-1β production through p38 activation and HIF-1α expression.
abstract: Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that plays a major role in inflammatory diseases as well as cancer. The inflammatory response after Toll-like receptor (TLR) 4 activation is tightly regulated through phosphorylation of MAP kinases, including p38 and JNK pathways. The activation of MAP kinases is negatively regulated by MAPK phosphatases (MKPs). MKP-1 preferentially dephosphorylates p38 and JNK. IL-1β is regulated through the activation of MAPK, including p38 as well as several transcription factors. The oxygen-sensitive transcription factor HIF-1α is a known transcription factor for several inflammatory cytokines including IL-1β and IL-6. Here, we report that MKP-1 regulates HIF-1α expression in response to LPS. MKP-1 deficient bone marrow derived macrophages (BMDMs) exhibited increased reactive oxygen species (ROS) production and higher HIF-1α expression. In contrast, the expression of all three isoforms of prolyl hydroxylases (PHDs), which are important in destabilizing HIF-1α through hydroxylation, were significantly decreased in MKP-1 deficient BMDMs. LPS challenge of MKP-1 deficient BMDMs led to a substantial increase in IL-1β production. An inhibitor of HIF-1α significantly decreased LPS mediated IL-1β production both at the transcript and protein levels. Similarly, inhibition of p38 MAP kinase reduced LPS mediated pro-IL-1β and HIF-1α protein levels as well as ROS production in MKP-1 deficient BMDMs. These findings demonstrate a regulatory function for MKP-1 in modulating IL-1β expression through p38 activation, ROS production and HIF-1α expression.
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Harvinder
authors.initials: H
authors.lastname: Talwar
authors.affiliation: Department of Pediatrics, Division of Critical Care, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Bauerfeld
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Bouhamdan
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Pershang
authors.initials: P
authors.lastname: Farshi
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, USA.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: ay6003@wayne.edu.
authors.forename: Lobelia
authors.initials: L
authors.lastname: Samavati
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004448:Echinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; D004448:Echinomycin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: BMDMs; DUSPs; HIF-1 α; IL-1β; MKP-1; Macrophages; p38