16996249

pubmed:Citation

2

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.

eng

IM

MEDLINE

0898-6568

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NLM

251-60

pubmed-meshheading:16996249-Activating Transcription Factors, pubmed-meshheading:16996249-Adrenergic beta-Agonists, pubmed-meshheading:16996249-Animals, pubmed-meshheading:16996249-Cell Line, pubmed-meshheading:16996249-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:16996249-Cytokines, pubmed-meshheading:16996249-Humans, pubmed-meshheading:16996249-Interleukin-1beta, pubmed-meshheading:16996249-Interleukin-6, pubmed-meshheading:16996249-Macrophages, pubmed-meshheading:16996249-Mice, pubmed-meshheading:16996249-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:16996249-NF-kappa B, pubmed-meshheading:16996249-Phosphorylation, pubmed-meshheading:16996249-Proto-Oncogene Proteins B-raf, pubmed-meshheading:16996249-RNA, Messenger, pubmed-meshheading:16996249-Receptors, Adrenergic, beta-2, pubmed-meshheading:16996249-Signal Transduction, pubmed-meshheading:16996249-Transfection, pubmed-meshheading:16996249-p38 Mitogen-Activated Protein Kinases

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

Journal Article, Research Support, N.I.H., Extramural