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J. Biol. Chem., Vol. 281, Issue 44, 33045-33052, November 3, 2006

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Modulation of Collagen and MMP-1 Gene Expression in Fibroblasts by the Immunosuppressive Drug Rapamycin

A DIRECT ROLE AS AN ANTIFIBROTIC AGENT?^*

Nicolas Poulalhon, Dominique Farge, Nina Roos, Charlotte Tacheau, Cindy Neuzillet, Laurence Michel, Alain Mauviel, and Franck Verrecchia¹

From the INSERM U697 and Service de Médecine Interne, Hôpital Saint-Louis, 75010 Paris, France

We have examined whether rapamycin, an immunosuppressive drug, may exert part of its antifibrotic activity by directly targeting fibroblast extracellular matrix deposition. Incubation of human lung fibroblast (WI-26) cultures with rapamycin led to dose- and time-dependent reduction in the expression of types I and III collagens, both at the protein and mRNA levels. Rapamycin had no effect on collagen promoter activity but accelerated mRNA decay, indicating post-transcriptional control of collagen gene expression. In contrast, rapamycin significantly enhanced the expression of interstitial collagenase (MMP-1) at the protein and mRNA levels and transcriptionally. We determined that rapamycin efficiently activates AP-1-driven transcription by rapidly inducing c-jun/AP-1 phosphorylation with activation of the c-Jun N-terminal kinase (JNK) cascade, resulting in enhanced binding of AP-1·DNA complex formation and AP-1-dependent gene transactivation. Conversely, the JNK inhibitor SP600125 inhibited rapamycin-induced MMP-1 gene transactivation and AP-1/DNA interactions. A c-jun antisense expression vector efficiently prevented rapamycin-induced MMP-1 gene transcription. Pharmacological inhibition of either ERK or p38 MAPK pathways was without effect on rapamycin-induced MMP-1 gene expression. It thus appears that rapamycin may exert direct antifibrotic activities independent from its immunosuppressive action.

Received for publication, July 5, 2006 , and in revised form, August 11, 2006.

^* This work was supported by the Groupe Français de Recherche sur la Sclérodermie (GFRS), the Association Française Contre la Sclérodermie (ASF), and INSERM (PNRDerm). 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 To whom correspondence should be addressed: INSERM U697, Hôpital Saint-Louis, Pavillon Bazin, 1 avenue Claude Vellefaux, 75010 Paris, France. Tel.: 33-153722076; Fax: 33-153722051; E-mail: franck.verrecchia{at}stlouis.inserm.fr.

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