S supported by National Natural Science Foundation of ChinaGrants 30872491/C160402, 81372552, and 81172349/H1617. Each authors contributed equally to this operate. 2 To whom correspondence may perhaps be addressed: Dept. of Apolipoprotein E/APOE Protein Biological Activity General Surgery, Research Center of Digestive Illnesses, Zhongnan Hospital of Wuhan University, Donghu Rd. 169, Wuhan 430071, China. Tel.: 86-27-68713007; Fax: 86-27-87330795; E-mail: spss2005@126. 3 To whom correspondence could be addressed: Dept. of General Surgery, Study Center of Digestive Illnesses, Zhongnan Hospital of Wuhan University, Donghu Rd. 169, Wuhan 430071, China. Tel.: 86-27-68713007; Fax: 86-27-87330795; E-mail: [email protected] hepatitis B virus (HBV)4 would be the most typical hepatitis virus, and it causes chronic infections in the human liver (1). Total eradication of HBV is seldom accomplished due to the persistence of its covalently closed circular DNA in host hepatocytes (two). A single crucial component from the host antiviral responses could be the interferon (IFN) technique. The immunomodulatory agent interferon (IFN- ) is recognized to decrease the quantity of covalently closed circular DNA, presumably by inducing T-cell cytotoxicity and lysis of infected hepatocytes, along with the production of cytokines for control of viral replication (3). Nevertheless, sufferers with chronic hepatitis B (CHB) usually respond poorly to IFN- treatment, as well as the underlying mechanism remains unclear (4). It is noteworthy that the HBV genome contains a specific DNA-binding website for the GR, and this HBV GR domain can be categorized as a functional glucocorticoid-response element (GRE). Therapy of CHB would benefit from an enhanced antiviral response to IFN- . An option approach to increase the efficacy and response rate observed with IFN may be to immunologically stimulate the host by withdrawing glucocorticoids (GCs) before therapy with IFN. In CHB infection, pulse GC therapy followed by abrupt withdrawal has been associated with an enhanced cellular immune response to hepatitis B, as indicated by a rise in alanine transaminase values along with a transient reduction in markers of viral replication upon withdrawal of GCs (five). Pretreatment with GCs (“immunologic priming”) is believed to become synergistic when followed by therapy with IFN- inside a subgroupThe abbreviations made use of are: HBV, hepatitis B virus; CHB, chronic hepatitis B; Dex, dexamethasone; DNMT, DNA methyltransferase; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid-response element; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBx, the X protein of hepatitis B virus; HCC, hepatocellular carcinoma; ISG, interferonstimulated genes; AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; nt, nucleotide.NOVEMBER 21, 2014 ?VOLUME 289 ?NUMBERJOURNAL OF BIOLOGICAL CHEMISTRYGC-induced AdoMet Enhances IFN Signalingof individuals (with low initial alanine transaminase values) (five, 6). While you will find distinct opinions concerning the rationale for a combination regimen of GCs and IFN- , most studies suggest that sequential remedy with GCs and IFN- for HBeAg-positive chronic hepatitis B could be additional productive than IFN- monotherapy in advertising the loss of hepatitis B “e” antigen and hepatitis B virus DNA (7). Having said that, the antiviral mechanism from the combination regimen is unknown. S-Adenosylmethionine (AdoMet), a principal biological IFN-beta, Human (CHO) methyl donor, is synthesized from methionine and ATP within a reaction catalyzed by methionine adenosyltransferase (eight, 9). In mammals.
