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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?

Abstract : 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.
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Contributor : Franck Verrecchia <>
Submitted on : Wednesday, August 1, 2007 - 10:31:12 AM
Last modification on : Wednesday, August 19, 2020 - 11:17:01 AM
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Nicolas Poulalhon, Dominique Farge, Nina Roos, Charlotte Tacheau, Cindy Neuzillet, et al.. Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent?. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (44), pp.33045-52. ⟨10.1074/jbc.M606366200⟩. ⟨inserm-00166115⟩

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