Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients
Richard Stratton, … , Carol M. Black, David Abraham
Richard Stratton, … , Carol M. Black, David Abraham
Published July 15, 2001
Citation Information: J Clin Invest. 2001;108(2):241-250. https://doi.org/10.1172/JCI12020.
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Article

Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

Abstract

Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud’s phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-β to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-β. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-β.

Authors

Richard Stratton, Xu Shiwen, Giorgia Martini, Alan Holmes, Andrew Leask, Thomas Haberberger, George R. Martin, Carol M. Black, David Abraham

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(a) Normal fibroblasts were grown to confluence on six-well plates and t...
(a) Normal fibroblasts were grown to confluence on six-well plates and treated with Iloprost (1 ng/ml) for various periods before lysis for cAMP measurement by enzyme immunoassay (gray bars). Other normal fibroblasts were treated with 2′,5′-DDA, an inhibitor of adenylate cyclase, for 2 hours before treatment with Iloprost (black bars). (b) Normal fibroblasts were treated with Iloprost at various concentrations for 30 minutes and then lysed for cAMP enzyme immunoassay (gray bars). Other normal fibroblasts were treated with TGF-β (10 ng/ml) for 2 hours before treatment with Iloprost, in order to determine whether Iloprost can elevate cAMP in the presence of TGF-β (black bars). (c) Normal fibroblasts were treated with TGF-β (10 ng/ml) with or without Iloprost (1 ng/ml) for 24 hours and before lysis for Western blot analysis for CTGF. Other normal fibroblasts were pretreated with 2′,5′-DDA for 2 hours before such treatment.