title: The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions.
abstract: Bioactive lipid mediators such as prostaglandin E2 (PGE2) have emerged as potent regulator of obese adipocyte inflammation and functions. PGE2 is produced by cyclooxygenases (COXs) from arachidonic acid, but inflammatory signaling pathways controlling COX-2 expression and PGE2 production in adipocytes remain ill-defined. Here, we demonstrated that the MAP kinase kinase kinase tumor progression locus 2 (Tpl2) controls COX-2 expression and PGE2 secretion in adipocytes in response to different inflammatory mediators. We found that pharmacological- or small interfering RNA-mediated Tpl2 inhibition in 3T3-L1 adipocytes decreased by 50% COX-2 induction in response to IL-1β, TNF-α, or a mix of the 2 cytokines. PGE2 secretion induced by the cytokine mix was also markedly blunted. At the molecular level, nuclear factor κB was required for Tpl2-induced COX-2 expression in response to IL-1β but was inhibitory for the TNF-α or cytokine mix response. In a coculture between adipocytes and macrophages, COX-2 was mainly increased in adipocytes and pharmacological inhibition of Tpl2 or its silencing in adipocytes markedly reduced COX-2 expression and PGE2 secretion. Further, Tpl2 inhibition in adipocytes reduces by 60% COX-2 expression induced by a conditioned medium from lipopolysaccharide (LPS)-treated macrophages. Importantly, LPS was less efficient to induce COX-2 mRNA in adipose tissue explants of Tpl2 null mice compared with wild-type and Tpl2 null mice displayed low COX-2 mRNA induction in adipose tissue in response to LPS injection. Collectively, these data established that activation of Tpl2 by inflammatory stimuli in adipocytes and adipose tissue contributes to increase COX-2 expression and production of PGE2 that could participate in the modulation of adipose tissue inflammation during obesity.
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Flavien
authors.initials: F
authors.lastname: Berthou
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Franck
authors.initials: F
authors.lastname: Ceppo
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Karine
authors.initials: K
authors.lastname: Dumas
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Massa
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Bastien
authors.initials: B
authors.lastname: Vergoni
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Alemany
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.affiliation: Inserm (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Unit 1065, Centre Méditerranéen de Médecine Moléculaire, Team 7 "Molecular and Cellular Physiopathology of Obesity and Diabetes," and Université Nice Sophia Antipolis (F.B., F.C., K.D., F.M., B.V., M.C., J.-F.T.), Centre Méditerranéen de Médecine Moléculaire, 06204 Cedex 3 Nice, France; and Instituto Investigaciones Biomédicas Alberto Sols (S.A.), Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28029 Madrid, Spain.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D053148:Caspase 3; D015232:Dinoprostone