title: Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes.
abstract: Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines such as interleukin-8 (IL-8) and interleukin-6 by human fibroblast-like synoviocytes from patients with rheumatoid arthritis (RAFLS). In those cells LPA was reported to induce IL-8 secretion through activation of various signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK), p42/44 MAPK, and Rho kinase. In addition to those pathways we report that mitogen- and stress-activated protein kinases (MSKs) known to be activated downstream of the ERK1/2 and p38 MAPK cascades and CREB are phosphorylated in response to LPA. The silencing of MSKs with small-interfering RNAs and the pharmacological inhibitor of MSKs SB747651A shows a role for both MSK1 and MSK2 in LPA-mediated phosphorylation of CREB at Ser-133 and secretion of IL-8 and MCP-1. Whereas CREB inhibitors have off target effects and increased LPA-mediated IL-8 secretion, the silencing of CREB1 with short hairpin RNA significantly reduced LPA-induced chemokine production in RAFLS. Taken together the data clearly suggest that MSK1 and MSK2 are the major CREB kinases in RAFLS stimulated with LPA and that phosphorylation of CREB1 at Ser-133 downstream of MSKs plays a significant role in chemokine production.
authors.affiliation: Rheumatology and Immunology Research Center, CHU de Québec Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Rheumatology and Immunology Research Center, CHU de Québec Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Weili
authors.initials: W
authors.lastname: Hui
authors.affiliation: Rheumatology and Immunology Research Center, CHU de Québec Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandes
authors.affiliation: Rheumatology and Immunology Research Center, CHU de Québec Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Patrice E
authors.initials: PE
authors.lastname: Poubelle
authors.affiliation: Rheumatology and Immunology Research Center, CHU de Québec Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada. Electronic address: sylvain.bourgoin@crchul.ulaval.ca.
authors.forename: Sylvain G
authors.initials: SG
authors.lastname: Bourgoin
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C111835:CCL2 protein, human; C115163:CREB1 protein, human; D018932:Chemokine CCL2; D017362:Cyclic AMP Response Element-Binding Protein; D016209:Interleukin-8; D008246:Lysophospholipids; D010069:Oxadiazoles; C570041:SB 747651A; D012694:Serine; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C032881:lysophosphatidic acid
keywords: Fibroblast-like synoviocytes; Interleukin-8; Lysophosphatidic acid; Mitogen- and stress-activated protein kinases; cAMP response element-binding protein