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J. Biol. Chem., Vol. 278, Issue 30, 27721-27728, July 25, 2003

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ERK 1/2- and JNKs-dependent Synthesis of Interleukins 6 and 8 by Fibroblast-like Synoviocytes Stimulated with Protein I/II, a Modulin from Oral Streptococci, Requires Focal Adhesion Kinase^*

Laurence Neff  , Mirjam Zeisel  , Vanessa Druet , Ken Takeda ¶, Jean-Paul Klein , Jean Sibilia || and Dominique Wachsmann  **

From the Laboratoire d'Immunologie et de Biochimie Bactérienne, Inserm U392, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch, the ^||Département de Rhumatologie, Hôpitaux Universitaires de Strasbourg, and the ^¶Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires-Unité Mixte de Recherche CNRS 7034, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch, France

Protein I/II, a pathogen-associated molecular pattern from oral streptococci, is a potent inducer of interleukin-6 (IL-6) and IL-8 synthesis and release from fibroblast-like synoviocytes (FLSs), cells that are critically involved in joint inflammation. This synthesis implicates ERK 1/2 and JNKs as well as AP-1-binding activity and nuclear translocation of NF-B. The mechanisms by which protein I/II activates MAPKs remain, however, elusive. Because focal adhesion kinase (FAK) was proposed to play a role in signaling to MAPKs, we examined its ability to contribute to the MAPKs-dependent synthesis of IL-6 and IL-8 in response to protein I/II. We used FAK–/– fibroblasts as well as FAK+/+ fibroblasts and FLSs transfected with FRNK, a dominant negative form of FAK. The results demonstrate that IL-6 and IL-8 release in response to protein I/II was strongly inhibited in both protein I/II-stimulated FAK–/– and FRNK-transfected cells. Cytochalasin D, which inhibits protein I/II-induced phosphorylation of FAK (Tyr-397), had no effect either on activation of ERK 1/2 and JNKs or on IL-6 and IL-8 release. Taken together, these results indicate that IL-6 and IL-8 release by protein I/II-activated FLSs is regulated by FAK independently of Tyr-397 phosphorylation.

Received for publication, November 26, 2002 , and in revised form, May 9, 2003.

^* This work was supported by grants from Amersham Biosciences, Wyeth Lederle, and Région Alsace. 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 33-3-90-24-41-52; Fax: 33-3-90-24-43-08; E-mail: wachs{at}pharma.u-strasbg.fr.

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