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<p>Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects most adults worldwide. Although frequently associated with acute hepatitis, no specific treatment for EBV-induced hepatitis currently exists. Using murine γ-herpesvirus 68 (MHV68) infection in mice, which is a well-established murine model for EBV infection, we previously demonstrated that MHV68-induced hepatitis is mediated via the Toll-like receptor 4 (TLR4) signaling pathway. In this study, we investigated the anti-hepatitis effects of two anti-inflammatory agents, ibudilast and dipyridamole, which are known to suppress LPS/TLR4-induced inflammation.&#xa0;In vitro antiviral activity was assessed in MHV68-infected 3T12 and MLE12 cells treated with ibudilast or dipyridamole (0–20&#xa0;µg/ml). Viral replication was measured by quantitative&#xa0;PCR, and cell viability was assessed via water-soluble tetrazolium assay. In vivo efficacy was evaluated in MHV68-infected C57BL/6 mice treated with ibudilast, dipyridamole, the TLR4 antagonist C34, or vehicle. Hepatitis was assessed by monitoring body weight and serum AST/ALT levels. Dipyridamole significantly reduced MHV68 replication in vitro at 10 and 20&#xa0;µg/ml without cytotoxicity. Ibudilast significantly reduced viral load; however, viral suppression was observed at cytotoxic concentrations. In vivo, both agents significantly reduced liver enzyme levels and mitigated body weight loss in infected mice. Their efficacy surpassed that of C34, a small-molecule TLR4 antagonist. Dipyridamole exhibited in vitro antiviral activity, and both agents effectively ameliorated MHV68-induced hepatitis in vivo. These findings highlight their therapeutic potential for acute hepatitis associated with extrahepatic viral infections, including EBV-associated disease.</p>

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Ibudilast and dipyridamole ameliorate murine γ-herpesvirus 68-induced acute hepatitis following airway infection

  • 期刊论文

  • 发表日期：

    2026年4月13日

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  • Koyuki Atifa Rahmi,
  • Hisashi Iizasa,
  • Hironori Yoshiyama,
  • Yusuke Endo,
  • Seiji Kageyama,
  • Kyosuke Kanai

摘要

Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects most adults worldwide. Although frequently associated with acute hepatitis, no specific treatment for EBV-induced hepatitis currently exists. Using murine γ-herpesvirus 68 (MHV68) infection in mice, which is a well-established murine model for EBV infection, we previously demonstrated that MHV68-induced hepatitis is mediated via the Toll-like receptor 4 (TLR4) signaling pathway. In this study, we investigated the anti-hepatitis effects of two anti-inflammatory agents, ibudilast and dipyridamole, which are known to suppress LPS/TLR4-induced inflammation. In vitro antiviral activity was assessed in MHV68-infected 3T12 and MLE12 cells treated with ibudilast or dipyridamole (0–20 µg/ml). Viral replication was measured by quantitative PCR, and cell viability was assessed via water-soluble tetrazolium assay. In vivo efficacy was evaluated in MHV68-infected C57BL/6 mice treated with ibudilast, dipyridamole, the TLR4 antagonist C34, or vehicle. Hepatitis was assessed by monitoring body weight and serum AST/ALT levels. Dipyridamole significantly reduced MHV68 replication in vitro at 10 and 20 µg/ml without cytotoxicity. Ibudilast significantly reduced viral load; however, viral suppression was observed at cytotoxic concentrations. In vivo, both agents significantly reduced liver enzyme levels and mitigated body weight loss in infected mice. Their efficacy surpassed that of C34, a small-molecule TLR4 antagonist. Dipyridamole exhibited in vitro antiviral activity, and both agents effectively ameliorated MHV68-induced hepatitis in vivo. These findings highlight their therapeutic potential for acute hepatitis associated with extrahepatic viral infections, including EBV-associated disease.