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 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-beta 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-beta. 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-beta.
Stratton
R
R
Centre for Rheumatology, Royal Free and University College Medical School, University College London, Royal Free Campus, London, United Kingdom.
Shiwen
X
X
Martini
G
G
Holmes
A
A
Leask
A
A
Haberberger
T
T
Martin
G R
GR
Black
C M
CM
Abraham
D
D
D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D004334:Drug Administration Schedule; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D016285:Iloprost / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D007262:Infusions, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D011453:Prostaglandins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011982:Receptors, Prostaglandin / Q000819:agonists; D012594:Scleroderma, Localized / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
C526317:CCN2 protein, human; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D003094:Collagen; D000242:Cyclic AMP; D016285:Iloprost