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Cross-Talk between G_s- and G_q-Coupled Pathways in Regulation of Interleukin-4 by A_2B Adenosine Receptors in Human Mast Cells

Divisions of Cardiovascular Medicine (A.E.G., I.F.) and Clinical Pharmacology (S.R., I.B.), Departments of Medicine (A.E.G., I.B., I.F.) and Pharmacology (S.R., I.B., I.F.), Vanderbilt University, Nashville, Tennessee

Human mast cells express functional A_2A and A_2B adenosine receptors. However, only stimulation of A_2B, not A_2A, leads to secretion of interleukin (IL)-4, an important step in adenosine receptor-mediated induction of IgE synthesis by B-cells. In this study, we investigate intracellular pathways that link stimulation of A_2B receptors to IL-4 up-regulation in HMC-1 mast cells. Both A_2A and A_2B receptors couple to G_s proteins and stimulate adenylate cyclase, but only A_2B stimulates phospholipase C through coupling to G_q proteins leading to activation of protein kinase C and calcium mobilization. Inhibition of phospholipase C completely blocked A_2B receptor-dependent IL-4 secretion. The protein kinase C inhibitor 2-{8-[(dimethylamino)-methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methyl-1H-indol-3-yl)maleimide (Ro-32-0432) had no effect on A_2B receptor-mediated IL-4 secretion but inhibited phorbol 12-myristate 13-acetate-stimulated IL-4 secretion. In contrast, chelation of intracellular Ca²⁺ inhibited both A_2B receptor- and ionomycin-dependent IL-4 secretion. This Ca²⁺-sensitive pathway probably includes calcineurin and nuclear factor of activated T cells, because A_2B receptor-dependent IL-4 secretion was blocked with cyclosporin A or 11R-VIVIT peptide. G_s-linked pathways also play a role in the A_2B receptor-dependent stimulation of IL-4 secretion; inhibition of adenylate cyclase or protein kinase A attenuated A_2B receptor-dependent IL-4 secretion. Although stimulation of adenylate cyclase with forskolin did not increase IL-4 secretion on its own, it potentiated the effect of Pasteurella multocida toxin by 2-fold and ionomycin by 3-fold. Both forskolin and stimulation of A_2B receptors up-regulated NFATc1 protein levels. We conclude that A_2B receptors up-regulate IL-4 through G_q signaling that is potentiated via cross-talk with G_s-coupled pathways.

Address correspondence to: Dr. Igor Feoktistov, 360 PRB, Vanderbilt University, Nashville, TN 37232-6300. E-mail: igor.feoktistov{at}vanderbilt.edu

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				S. Ryzhov, R. Zaynagetdinov, A. E. Goldstein, S. V. Novitskiy, M. M. Dikov, M. R. Blackburn, I. Biaggioni, and I. Feoktistov Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells J. Immunol., June 1, 2008; 180(11): 7212 - 7220. [Abstract] [Full Text] [PDF]

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