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.
Highlights
Fibrosis is a reactive process involving different pathophysiological events such as attraction of blood-born cells, alteration of the microvasculature, and activation of resident mesenchymal cells leading to excessive extracellular matrix (ECM)2 deposition [1,2,3,4]
To assess the role played by MAPKs in mediating rapamycindriven induction of matrix metalloproteinase (MMP)-1 gene expression, we investigated the ability of specific inhibitors of the Jun N-terminal kinase (JNK), p38, and ERK pathways to alter rapamycin-driven MMP-1 gene expression
We provide evidence that the immunosuppressive drug rapamycin, an inhibitor of mTOR, may exert direct antifibrotic activities both by down-regulating type I and type III collagen synthesis and by up-regulating MMP-1 synthesis
Summary
We have examined whether rapamycin, an immunosuppressive drug, may exert part of its antifibrotic activity by directly targeting fibroblast extracellular matrix deposition. Identifying molecules that may either affect collagen production negatively or MMP expression positively is of utmost importance to define novel therapeutic means against fibrosis. In this context, rapamycin (sirolimus), a Streptomyces fungus macrolide antibiotic with potent immunosuppressive properties, is currently used for the prevention of graft rejection in kidney transplant recipients [5,6,7]. We identify distinct mechanisms by which rapamycin modulates both the expression of fibrillar collagen genes and that of interstitial collagenase/MMP-1.
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