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Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes.

Publication ,  Journal Article
Tchivileva, IE; Tan, KS; Gambarian, M; Nackley, AG; Medvedev, AV; Romanov, S; Flood, PM; Maixner, W; Makarov, SS; Diatchenko, L
Published in: Mol Immunol
July 2009

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.

Duke Scholars

Published In

Mol Immunol

DOI

EISSN

1872-9142

Publication Date

July 2009

Volume

46

Issue

11-12

Start / End Page

2256 / 2266

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Signal Transduction
  • Response Elements
  • Receptors, Adrenergic, beta-3
  • Protein Kinase C
  • NF-kappa B
  • Mice
  • Interleukin-6
  • Immunology
  • Humans
 

Citation

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Tchivileva, I. E., Tan, K. S., Gambarian, M., Nackley, A. G., Medvedev, A. V., Romanov, S., … Diatchenko, L. (2009). Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol Immunol, 46(11–12), 2256–2266. https://doi.org/10.1016/j.molimm.2009.04.008
Tchivileva, Inna E., Kai Soo Tan, Maria Gambarian, Andrea G. Nackley, Alexander V. Medvedev, Sergei Romanov, Patrick M. Flood, William Maixner, Sergei S. Makarov, and Luda Diatchenko. “Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes.Mol Immunol 46, no. 11–12 (July 2009): 2256–66. https://doi.org/10.1016/j.molimm.2009.04.008.
Tchivileva IE, Tan KS, Gambarian M, Nackley AG, Medvedev AV, Romanov S, et al. Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol Immunol. 2009 Jul;46(11–12):2256–66.
Tchivileva, Inna E., et al. “Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes.Mol Immunol, vol. 46, no. 11–12, July 2009, pp. 2256–66. Pubmed, doi:10.1016/j.molimm.2009.04.008.
Tchivileva IE, Tan KS, Gambarian M, Nackley AG, Medvedev AV, Romanov S, Flood PM, Maixner W, Makarov SS, Diatchenko L. Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol Immunol. 2009 Jul;46(11–12):2256–2266.
Journal cover image

Published In

Mol Immunol

DOI

EISSN

1872-9142

Publication Date

July 2009

Volume

46

Issue

11-12

Start / End Page

2256 / 2266

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Signal Transduction
  • Response Elements
  • Receptors, Adrenergic, beta-3
  • Protein Kinase C
  • NF-kappa B
  • Mice
  • Interleukin-6
  • Immunology
  • Humans