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J. Biol. Chem., Vol. 283, Issue 4, 1974-1984, January 25, 2008

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Signaling by the Cysteinyl-Leukotriene Receptor 2

INVOLVEMENT IN CHEMOKINE GENE TRANSCRIPTION^*

Charles Thompson, Alexandre Cloutier, Ynuk Bossé, Caroline Poisson, Pierre Larivée, Patrick P. McDonald, Jana Stankova, and Marek Rola-Pleszczynski¹

From the Immunology Division, Department of Pediatrics, and Pulmonary Division, Department of Medicine, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada

Cysteinyl-leukotrienes are involved in inflammation and act on at least two G-protein-coupled receptors, CysLT1 and CysLT2. However, the role of the CysLT2 receptor as well as its signaling remain poorly understood. Here we show that leukotriene (LT)C₄ induced the production of the chemokine interleukin (IL)-8 in endothelial cells. To further study the signaling cascade involved, HEK293 cells were stably transfected with CysLT2 and used to study the transcriptional regulation of the IL-8 promoter. Stimulation of the cells with increasing concentrations of LTC₄ resulted in a time- and concentration-dependent induction of IL-8 transcription and protein synthesis. Use of IL-8 promoter mutants with substitutions in their NF-B, AP-1, or NF-IL-6 binding elements revealed an almost total requirement for NF-B and AP-1 elements, and a lesser requirement for the NF-IL-6 element. Overexpression of dominant-negative IB prevented the IL-8 transactivation induced by LTC₄. LTC₄ stimulation induced NF-B and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN·c-FOS complex, respectively. Transfection of the cells with a dominant negative (dn) form of PKC prevented p65 phosphorylation, whereas dnPKC prevented AP-1 binding. Moreover, dnPKC, dnPKC, and dnPKC prevented LTC₄-induced IL-8 transcription in response to LTC₄. Our data show for the first time that LTC₄ can act via the CysLT2 receptor to transcriptionally activate chemokine production through induction of NF-B and AP-1 transcription factors. These findings suggest the potential implication of CysLT2 in the inflammatory response through the modulation of chemokine gene transcription.

Received for publication, August 25, 2006 , and in revised form, November 18, 2007.

^* This work was supported in part by grants (to P. P. McD., J. S., and M. R.-P.) and studentships (to C. T., A. C., and Y. B.) from the Canadian Institutes of Health Research and a grant from the Foundation for Research into Children's Diseases. 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 Recipient of a Canada Research Chair in Inflammation. To whom correspondence should be addressed: 3001 North 12th Ave., Sherbrooke, Quebec J1H 5N4, Canada. Tel.: 819-346-1110 (ext: 14851); Fax: 819-564-5215; E-mail: marek.rola-pleszczynski{at}usherbrooke.ca.

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