The orphan receptor COUP-TF II (Arp-1) is required for stellate cells activation and is involved in mitogenic responses in activated cells.

as the precursor cell type mainly responsible for the development of liver fibrosis. Although physiological mechanisms controlling HSC fibrogenesis and proliferation have been studied intensively, the intracellular signals regulating the transformation of HSC into myofibroblast-like cells remain uncertain. We recently showed that nuclear receptor PPARy is rapidly down regulated during HSC activation and its ligand dependent and independent activation restore quiescent phenotype. Studying the mechanisms involved in PPARy expression in HSC we found that the orphan receptors Chicken Ovoalbumin Upstream Promoter Transcription Factors (COUP-TFs) regulate PPARy promoter activity. Further more there are evidences that COUP-TFs modulate the activity of other nuclear receptors including retinoic acid receptors (RARs) and estrogen receptors (ERs). Aim. In consideration of the role of nuclear receptors in HSC physiology we analyzed the expression and activity of COUP-TF receptors during HSC activation in vitro and their transcriptional regulation in activated cells. Methods. Expression of COUP-TFs was evaluated by western blot and RTPCR in quiescent and activated HSC. Trancriptional activity was monitored by transfection experiment using a luciferase reporter plasmid specific for COUP-TF (-8411-800 NHE-1 promoter). HSC proliferation and and motility were evaluated by 3H-tymidine incorporation and invasion assay in Boyden chambers respectively. Results. COUP-TF I1 (Arp-1) but not COUP-TF I was rapidly up regulated during HSC transdifferentiation in vitro. In freshly isolated cells both receptors were undetectable but after THE ORPHAN RECEPTOR COUP-TF I1 (ARP-1) IS REQUIRED 24h on plastic COUP-TF I1 was significantly increased. In parallel transcriptional activity was induced during cell activation. In activated HSC increased COUP-TF transcriptional activity obtained by co-trasfection with hCOUP-TF I1 expression plasmid, significantly increased HSC proliferation and migration and augmented response to mitogens such as PDGF and EGF. In addition COUP-TF I1 antagonized PPARy transcriptional activity and induced AP-1 via a strong induction of c-fosljun B expression. Finally both COUP-TF I1 dominant negative and specific COUP-TF I1 siRNA completely abrogated growth factors induced migration and proliferation and restored HSC quiescent phenotype. In conclusion these data suggested that members of COUP-TF family of transcription factors play a significant role in modulating profibrogenic response in human HSC. The following authors have indicated they have no relationships