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J. Biol. Chem., Vol. 279, Issue 34, 35183-35192, August 20, 2004

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STAT6 and Ets-1 Form a Stable Complex That Modulates Socs-1 Expression by Interleukin-4 in Keratinocytes^*

Julia Travagli, Martine Letourneur, Jacques Bertoglio, and Josiane Pierre

From the INSERM U461, Faculté de pharmacie, 5 Rue J. B. Clément, 92296-Chatenay-Malabry, France

Supressor of cytokine signaling (SOCS)-1 is selectively and rapidly induced by appropriate agonists and modulates cytokine responses by interfering with the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. On the basis of the observation that interleukin (IL)-4 up-regulates Socs-1 in the keratinocyte HaCaT cell line, we investigated which sequences of the 5'-Socs-1 gene are responsive to IL-4. We therefore have cloned the 5'-flanking region of this gene, and by promoter analysis we identified a functional IL-4-responsive element located at nucleotide (–684/–570) upstream from the transcription initiation site, whose presence and integrity are necessary to ensure IL-4 responsiveness. This element contains three STAT6 and one Ets consensus binding sequences of which specific mutations abolished IL-4 responsiveness either partially or totally. We also report that Ets-1 physically interacted with STAT6. Exogenous expression of Ets-1 in conjunction with STAT6 activation strongly inhibited expression of a Socs-1 promoter-luciferase reporter. Collectively, our data demonstrated the involvement of STAT6 and Ets, via a composite DNA element, in the IL-4 regulation of Socs-1 gene expression in keratinocytes.

Received for publication, March 23, 2004 , and in revised form, May 11, 2004.

^* 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.

A recipient of a fellowship from the Ligue Nationale contre le Cancer (Comité du Cher).

To whom correspondence should be addressed. Tel.: 33-1-46835483; Fax: 33-1-46835496; E-mail: josiane.pierre{at}cep.u-psud.fr.

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