title: 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.
authors.affiliation: INSERM U697, Hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poulalhon
authors.forename: Dominique
authors.initials: D
authors.lastname: Farge
authors.forename: Nina
authors.initials: N
authors.lastname: Roos
authors.forename: Charlotte
authors.initials: C
authors.lastname: Tacheau
authors.forename: Cindy
authors.initials: C
authors.lastname: Neuzillet
authors.forename: Laurence
authors.initials: L
authors.lastname: Michel
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
mesh_terms: D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D024042:Collagen Type I; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D020123:Sirolimus