Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms.

Published

Journal Article

Activation of the beta(2) adrenergic receptor (beta(2)AR) located on macrophages has been reported to possess anti-inflammatory properties, inhibiting nuclear factor kappaB (NF-kappaB) activation and cytokine production induced by pro-inflammatory stimuli. Here, we show that activation of the beta(2)AR in the absence of pro-inflammatory stimuli produced up to an 80- and 8-fold increase in IL-1beta and IL-6 transcripts, respectively, in the RAW 264.7 murine macrophage cell line. This increase in mRNA expression was accompanied by a significant increase in IL-1beta and IL-6 protein production. Pre-treatment of RAW cells with pharmacological inhibitors of protein kinase A (PKA) or NF-kappaB pathway failed to block this cytokine increase. Instead, the beta(2)AR-mediated increase in cytokines required activation of both the B-raf-ERK1/2 and p38 pathways. Treatment of RAW cells with the exchange protein directly activated by cAMP (EPAC) agonist also resulted in the up-regulation of IL-1beta and IL-6 transcripts. Examination of the main transcription factors downstream of the ERK1/2 and p38 signaling revealed that beta(2)AR activation resulted in the stimulation of CRE-, but not C/EBPbeta-, ETS-, or NF-kappaB-dependent transcription. Western blot analysis further showed that among the transcription factors which recognize the CRE-binding site, ATF-1 and ATF-2 but not CREB proteins were phosphorylated in an ERK1/2- and p38-dependent manner. Collectively, these results demonstrate that beta(2)ARs possess pro-inflammatory properties and that their activation leads to IL-1beta and IL-6 production through ERK1/2- and p38-dependent activation of ATF-1 and ATF-2 transcription factors.

Full Text

Duke Authors

Cited Authors

  • Tan, KS; Nackley, AG; Satterfield, K; Maixner, W; Diatchenko, L; Flood, PM

Published Date

  • February 2007

Published In

Volume / Issue

  • 19 / 2

Start / End Page

  • 251 - 260

PubMed ID

  • 16996249

Pubmed Central ID

  • 16996249

Electronic International Standard Serial Number (EISSN)

  • 1873-3913

International Standard Serial Number (ISSN)

  • 0898-6568

Digital Object Identifier (DOI)

  • 10.1016/j.cellsig.2006.06.007

Language

  • eng