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J. Biol. Chem., Vol. 281, Issue 18, 12421-12427, May 5, 2006

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The cGMP/Protein Kinase G Pathway Contributes to Dihydropyridine-sensitive Calcium Response and Cytokine Production in TH2 Lymphocytes^*

Bruno Gomes, Magali Savignac¹, Marilena Djata Cabral¹, Pierre Paulet, Marc Moreau, Catherine Leclerc, Robert Feil^¶, Franz Hofmann^¶, Jean-Charles Guéry, Gilles Dietrich, and Lucette Pelletier²

From the INSERM, 1U563, Centre de Physiopathologie de Toulouse Purpan, F-31024 Toulouse Cedex 3, France, CNRS, Unite Mixte de Recherche 5547, Université Paul-Sabatier, F-31062 Toulouse Cedex 4, France, and ^¶Institut für Pharmakologie und Toxikologie der Technischen Universität München, G-80802 München, Germany

Th2 lymphocytes differ from other CD4⁺ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca²⁺]_i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.

Received for publication, September 29, 2005 , and in revised form, January 23, 2006.

^* This work was supported by grants from the Ligue contre le Cancer, the Association pour la Recherche sur la Polyarthrite Rhumatoide, INSERM (progamm Progres), Agence Nationale pour la Recherche, the Association de Recherche contre le Cancer (to B. G. and M. S.), and la Fundaçao Calouste Gulbenkian (to M. D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: INSERM U563, CHU Purpan, Place du Dr Baylac, Dept. of Genetics, Pavillon Lefebvre, BP 3028, 31024 Toulouse Cedex 3, France. Tel.: 33-5-62-74-45-01; Fax: 33-5-62-74-45-58; E-mail: Lucette.Pelletier{at}toulouse.inserm.fr.

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