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Prostacyclin derivatives prevent the fibrotic response to TGFβ2 by inhibiting the Ras/MEK/ERK pathway
Author(s) -
Stratton Richard,
Rajkumar Vineeth,
Ponticos Markella,
Nichols Blake,
Shiwen Xu,
Black Carol M.,
Abraham David J.,
Leask Andrew
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0204fje
Subject(s) - mapk/erk pathway , smad , ctgf , growth factor , cancer research , signal transduction , transforming growth factor , chemistry , microbiology and biotechnology , mek inhibitor , medicine , endocrinology , biology , receptor
The SMAD‐mediated induction of connective tissue growth factor (CTGF), a fibroproliferative cytokine, by transforming growth factor (TGF)β is required for the development of sustained fibrosis in humans. Here, we show that in fibroblasts, activation of the Ras/MEK/ERK pathway is required for the SMAD‐mediated induction of CTGF by TGFβ2. We then show that activation of protein kinase A (PKA) in fibroblasts is able to block Ras/MEK/ERK signaling and abolish the fibrotic response. Previously, we found that prostacyclin agonists were able to prevent the induction of CTGF in fibroblasts, and in patients with the fibrotic disease scleroderma. Here, we confirm the in vitro and in vivo antifibrotic effects of prostacyclin derivatives and show that these effects are due to PKA‐dependent inhibition of the Ras/MEK/ERK pathway. Ras/MEK/ERK does not directly affect SMAD signaling. The coordinate and varied biological responses to TGFβ are in part due to the interactions of signaling pathways within target cells. Specific inhibition of fibroblast Ras/MEK/ERK signaling might prevent fibrosis while leaving other physiological effects of TGFβ unaltered.