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Prostacyclin derivatives prevent the fibrotic response to TGF beta 2 by inhibiting the Ras/MEK/ERK pathway

Stratton, R; Rajkumar, V; Ponticos, M; Nichols, B; Xu, SW; Black, CM; Abraham, DJ; (2002) Prostacyclin derivatives prevent the fibrotic response to TGF beta 2 by inhibiting the Ras/MEK/ERK pathway. FASEB J , 16 (12) 1949 - +. 10.1096/fj.02-0204fje.

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Abstract

The SMAD-mediated induction of connective tissue growth factor (CTGF), a fibroproliferative cytokine, by transforming growth factor (TGF)beta 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 TGFbeta2. 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 TGFbeta 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 TGFbeta unaltered.

Type: Article
Title: Prostacyclin derivatives prevent the fibrotic response to TGF beta 2 by inhibiting the Ras/MEK/ERK pathway
DOI: 10.1096/fj.02-0204fje
Keywords: MAP kinase, SMAD, CTGF, iloprost, GROWTH-FACTOR-BETA, GENE-EXPRESSION, SCLERODERMA FIBROBLASTS, SYSTEMIC-SCLEROSIS, EPITHELIAL-CELLS, PROTEIN-KINASES, RAF-1 KINASE, ACTIVATION, SMAD, CAMP
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/190909
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