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

Cell Signal. 2007 Feb;19(2):251-60. doi: 10.1016/j.cellsig.2006.06.007. Epub 2006 Sep 20.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Activating Transcription Factors
  • Adrenergic beta-Agonists
  • Cytokines
  • Interleukin-1beta
  • Interleukin-6
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Adrenergic, beta-2
  • Proto-Oncogene Proteins B-raf
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases