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.

Prostaglandin I2analogues enhance already exuberant Th17 cell responses in systemic sclerosis

“…The PGI 2 analogue iloprost is effective in ameliorating digital ulcers (DU), which affect a high proportion of individuals with SSc 16. In addition, iloprost displays in vitro antifibrotic properties17 and may have beneficial effects on the course of SSc in a subgroup of patients 18 19…”

Iloprost modulates the immune response in systemic sclerosis

“…It has been suggested that iloprost reduces skin fibrosis by reducing collagen synthesis [13,14], the pro-fibrotic cytokine connective tissue growth factor [15] and the fibrotic response [16]. …”

Morphea simulating paucibacillary leprosy clinically and histopathologically

“…Those alterations appear to lead to increased connective tissue growth factor (CTGF) gene expression and finally fibrosis. [45] Immunological cytokines, auto-immune, trauma, immobility, radiotherapy, hormonal and infection etiology mainly with Borrelia burgdorferi also have been reported. [6]…”