title: Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes.
abstract: The beta(3)-adrenergic receptor (beta(3)AR) is an essential regulator of metabolic and endocrine functions. A major cellular and clinically significant consequence of beta(3)AR activation is the substantial elevation in interleukin-6 (IL-6) levels. Although the beta(3)AR-dependent regulation of IL-6 expression is well established, the cellular pathways underlying this regulation have not been characterized. Using a novel method of homogenous reporters, we assessed the pattern of activation of 43 transcription factors in response to the specific beta(3)AR agonist CL316243 in adipocytes, cells that exhibit the highest expression of beta(3)ARs. We observed a unique and robust activation of the CRE-response element, suggesting that IL-6 transcription is regulated via the G(s)-protein/cAMP/protein kinase A (PKA) but not nuclear factor kappa B (NF-kappaB) pathway. However, pretreatment of adipocytes with pharmacologic inhibitors of PKA pathway failed to block beta(3)AR-mediated IL-6 up-regulation. Additionally, stimulation of adipocytes with the exchange protein directly activated by cAMP (Epac) agonist did not induce IL-6 expression. Instead, the beta(3)AR-mediated transcription of IL-6 required activation of both the p38 and PKC pathways. Western blot analysis further showed that transcription factors CREB and ATF-2 but not ATF-1 were activated in a p38- and PKC-dependent manner. Collectively, our results suggest that while stimulation of the beta(3)AR leads to a specific activation of CRE-dependent transcription, there are several independent cellular pathways that converge at the level of CRE-response element activation, and in the case of IL-6 this activation is mediated by p38 and PKC but not PKA pathways.
authors.affiliation: The Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA. tchivilei@dentistry.unc.edu
authors.forename: Inna E
authors.initials: IE
authors.lastname: Tchivileva
authors.forename: Kai Soo
authors.initials: KS
authors.lastname: Tan
authors.forename: Maria
authors.initials: M
authors.lastname: Gambarian
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Nackley
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Medvedev
authors.forename: Sergei
authors.initials: S
authors.lastname: Romanov
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Flood
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Sergei S
authors.initials: SS
authors.lastname: Makarov
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D020218:Response Elements; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; D058667:Adrenergic beta-3 Receptor Agonists; D004149:Dioxoles; D015850:Interleukin-6; D016328:NF-kappa B; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs