Melanoma Differentiation-Associated Gene 5 Regulates the Expression of a Chemokine CXCL10 in Human Mesangial Cells: Implications for Chronic Inflammatory Renal Diseases

Abstract

Mesangial cells play an important role in inflammatory reactions in kidney. Although viral infections often trigger the worsening of chronic inflammatory renal diseases, the mechanisms are largely unknown. Melanoma differentiation-associated gene 5 (MDA5) is a member of RNA helicase family with a conserved Asp-Glu-x-His (DExH) box. In the present study, we examined the effect of polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA (dsRNA) that mimics viral dsRNAs, on MDA5 expression using primary culture of human mesangial cells. The cells were simply treated or transfected with poly IC; the former procedure is a model of cells exposed to viral dsRNA released from dying cells, and the latter is a model of entry of RNA virus into the cytoplasm. Expression levels of MDA5 mRNA in mesangial cells were increased about 70-100 fold in response to either treatment or transfection with poly IC. MDA5 protein expression was significantly induced as well. RNA interference experiments revealed that poly IC treatment induced MDA5 expression via Toll-like receptor 3 (TLR3) and interferon (IFN)-β, and that poly IC trasnfection induced MDA5 expression via another DExH box RNA helicase, retinoic acid-inducible gene-I (RIG-I), and IFN-β. Moreover, MDA5 induced by poly IC, in turn, increased the expression of a chemokine CXCL10. In addition, immunohistochemical staining demonstrated a high level of MDA5 expression in glomeruli, mainly in mesangial cells, of patients with severe lupus nephritis or proteinuric IgA nephropathy. MDA5 may be involved not only in physiological antiviral reactions but also in chronic inflammation in glomerular mesangial cells.