tgf-β and iron differently alter hbv replication in human hepatocytes through tgf-βbmp signaling and cellular microrna expressiontgf-β和铁的不同改变乙肝病毒复制在人类肝细胞通过tgf-βbmp信号和细胞微rna表达.pdf

TGF-b and Iron Differently Alter HBV Replication in Human Hepatocytes through TGF-b/BMP Signaling and Cellular MicroRNA Expression 1 1 1,2,3 Sun O. Park , Mukesh Kumar , Sanjeev Gupta * 1 Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America, 2 Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America, 3 Marion Bessin Liver Research Center, Cancer Center, Diabetes Research Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and Institute for Clinical and Translational Research, Bronx, New York, United States of America Abstract The nature of host-virus interactions in hepatitis B virus infection is incompletely understood. Since soluble factors, e.g., cytokines and metals, may exacerbate liver injury in chronic hepatitis, we considered that defining the effects of receptor- mediated signaling upon viral replication will be significant. Consequently, we studied effects of iron or TGF-b-induced TGF- b/BMP signaling in the HepG2 2.2.15 cell model of hepatitis B virus replication. We found iron and TGF- b increased hepcidin mRNA expression or TGF-b receptor kinase activity, respectively, which indicated that 2.2.15 cells responded appropriately to these substances. However, iron increased but TGF-b decreased hepatitis B virus mRNA and DNA expression. TGF-b induced expression at the mRNA level of multiple TGF-b/BMP pathway genes. This change was not observed in iron-treated cells. On the other hand, presence of SMAD proteins in iron or TGF-b-treated cells, including of SMAD4, did confirm convergence of TGF-b/BMP signaling pathways under these conditions. Since tran