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

Patients with scleroderma receiving Iloprost as a treatment for severe Rayn aud's phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis, Connective tissue growth factor (CTGF), a rec ently described profibrotic cytokine, acts downstream and in concert with T GF-beta to stimulate the fibrotic process and is involved in the fibrosis s een in scleroderma. Here we show that Iloprost, acting by elevation of cAMP , blocks the induction of CTGF and the increase in collagen synthesis in fi broblasts exposed to TGF-beta. The potency of Iloprost with respect to supp ression of CTGF Far exceeds that of other prostanoid receptor agonists, sug gesting that its effect is mediated by the prostacyclin receptor IF. By sam pling dermal interstitial fluid using a suction blister device, we show tha t CTGF levels are greatly elevated in the dermis of scleroderma patients co mpared with healthy controls and that Iloprost infusion causes a marked dec rease in dermal CTGF levels. These studies suggest that Iloprost could be r educing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-beta.