Response gene to complement 32 mediate TGF-beta induced production of extracellular matrix by astrocytes (44.16)

Abstract

Abstract Later stages of multiple sclerosis (MS) are characterized by a reduced number of inflammatory cells and an excessive accumulation of extracellular matrix (ECM) components, which leads to tissue fibrosis. Profibrotic cytokines such as TGF-beta stimulate the synthesis of ECM by astrocytes. However, the intracellular mechanism by which TGF-beta stimulates the production of ECM is not completely understood. We have identified Response Gene to Complement (RGC)-32 as a factor induced by complement activation, growth factors, cytokines and TGF-beta. In view of the important role of TGF-beta in promotion of gliosis, we sought to determine whether RGC-32 plays a role in TGF-beta induced gliosis. RGC-32 was expressed at low levels in unstimulated astrocytes. After 3 h of TGF-beta stimulation, mRNA expression was significantly increased and after 18 h of treatment both the RGC-32 mRNA and protein expression levels were robustly increased when compared with controls. RGC-32 knockdown resulted in a significant reduction in procollagen I, procollagen II and fibronectin expression induced by TGF-beta. In addition, using chromatin immunoprecipitation assay we have shown the in vivo binding of RUNX1 to the RGC-32 promoter after TGF-beta stimulation. Taken together, our data demonstrate for the first time that RGC-32 plays a critical role in TGF-beta-induced ECM production in astrocytes. Our study suggests that RGC-32 can be a new target for therapeutic intervention to prevent gliosis in MS.