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Molecular and Cellular Biology, September 2006, p. 6333-6346, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00207-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Exchange Protein Activated by Cyclic AMP (Epac)-Mediated Induction of Suppressor of Cytokine Signaling 3 (SOCS-3) in Vascular Endothelial Cells

William A. Sands, Hayley D. Woolson, Gillian R. Milne, Claire Rutherford, and Timothy M. Palmer*

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Received 6 February 2006/ Returned for modification 28 March 2006/ Accepted 8 June 2006

Here, we demonstrate that elevation of intracellular cyclic AMP (cAMP) in vascular endothelial cells (ECs) by either a direct activator of adenylyl cyclase or endogenous cAMP-mobilizing G protein-coupled receptors inhibited the tyrosine phosphorylation of STAT proteins by an interleukin 6 (IL-6) receptor trans-signaling complex (soluble IL-6R{alpha}/IL-6). This was associated with the induction of suppressor of cytokine signaling 3 (SOCS-3), a bona fide inhibitor in vivo of gp130, the signal-transducing component of the IL-6 receptor complex. Attenuation of SOCS-3 induction in either ECs or SOCS-3-null murine embryonic fibroblasts abolished the inhibitory effect of cAMP, whereas inhibition of SHP-2, another negative regulator of gp130, was without effect. Interestingly, the inhibition of STAT phosphorylation and SOCS-3 induction did not require cAMP-dependent protein kinase activity but could be recapitulated upon selective activation of the alternative cAMP sensor Epac, a guanine nucleotide exchange factor for Rap1. Consistent with this hypothesis, small interfering RNA-mediated knockdown of Epac1 was sufficient to attenuate both cAMP-mediated SOCS-3 induction and inhibition of STAT phosphorylation, suggesting that Epac activation is both necessary and sufficient to observe these effects. Together, these data argue for the existence of a novel cAMP/Epac/Rap1/SOCS-3 pathway for limiting IL-6 receptor signaling in ECs and illuminate a new mechanism by which cAMP may mediate its potent anti-inflammatory effects.

* Corresponding author. Mailing address: 425 Davidson Bldg., Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom. Phone: 44 141 330 4626. Fax: 44 141 330 4620. E-mail: T.Palmer{at}bio.gla.ac.uk.

Molecular and Cellular Biology, September 2006, p. 6333-6346, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00207-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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