The role of the RNA binding protein KSRP in pro-inflammatory gene expression

点击翻译按钮获取中文摘要

Human chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), asthma, diabetes or atherosclerosis are characterized by a dysregulated expression of pro-inflammatory genes. The expression of these genes is regulated on the post-transcriptional level, primarily. AU-rich elements located in the 3'-untranslated region of those mRNAs are centrally involved in these processes. RNA binding proteins (RNA-BP) bind to these sequence elements and modulate stability, translatability and localization of the mRNAs. We demonstrated that KSRP plays a major role in the post-transcriptional regulation of the expression of the pro-inflammatory enzyme human inducible NO synthase.In the last funding period we identified in human chondrocytes several mediators of chronic inflammatory diseases (like MMP3, MMP9, RANTES) as new KSRP-target mRNAs. In the model of collagen-induced arthritis (CIA, RA model) and in MRL-FASlpr mice (SLE model) we detected a negative correlation between the expression of KSRP and pro-inflammatory genes.Meanwhile, we established the breeding of mice with inactivated KSRP gene (KSRP-/--mice, obtained from Dr. Chen) in our lab. In these mice we confirmed in-vivo and in primary cells the KSRP-mediated regulation of IL-8-, iNOS and TNF-alpha expression. Molecular analyses showed an autoregulation of KSRP expression in human cells. Recent work of our group indicated that the anti-inflammatory effects of resveratrol could be explained by a direct binding of this phytoalexin to KSRP. This interaction resulted in enhanced activity of the KSRP protein.In the next funding period we want to examine the effects of altered KSRP expression in chronic inflammatory diseases in vivo using the KSRP-/--mice model. To analyze the effects of inactivation of the KSRP gene on disease progression and severity we will establish CIA and SLE models in those mice. In these models we will study the role of KSRP in immunological processes. In addition we want to analyze in-vivo whether resveratrol performs its anti-inflammatory effects via modulation of KSRP activity. Another focus of the planned project is to understand the molecular mechanisms regulating the expression of KSRP in chronic inflammatory diseases. Moreover in blood cells from RA and SLE patients we want to determine whether the results obtained in our in-vitro and animal models could be translated to the human system.