Hepatitis B virus replication could enhance regulatory T cell activity by producing soluble heat shock protein 60 from hepatocytes

Yasuteru Kondo, Yoshiyuki Ueno, Koju Kobayashi, Eiji Kakazu, Masaaki Shiina, Jun Inoue, Keiichi Tamai, Yuta Wakui, Yasuhito Tanaka, Masashi Ninomiya, Noriyuki Obara, Koji Fukushima, Motoyasu Ishii, Tomoo Kobayashi, Hirofumi Niitsuma, Satonori Kon, Tooru Shimosegawa

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background. HBcAg-specific regulatory T (Treg) cells play an important role in the pathogenesis of chronic hepatitis B. Soluble heat shock proteins, especially soluble heat shock protein 60 (sHSP60), could affect the function of Treg cells via Toll-like receptor. Methods. We analyzed the relationship between soluble heat shock protein production and hepatitis B virus (HBV) replication with both clinical samples from HBeAg-positive patients with chronic hepatitis B (n=24) and HBeAb-positive patients with chronic hepatitis B (n=24) and in vitro HBV-replicating hepatocytes. Thereafter, we examined the biological effects of sHSP60 with isolated Treg cells. Results. The serum levels of sHSP60 in patients with chronic hepatitis B were statistically significantly higher than those in patients with chronic hepatitis C (P < .01), and the levels of sHSP60 were correlated with the HBV DNA levels (R=0.532; P < .001) but not with the alanine aminotransferase levels. Moreover, the levels of sHSP60 in HBV-replicating HepG2 cells were statistically significantly higher than those in control HepG2 cells. Preincubation of CD4+ CD25+ cells with recombinant HSP60 (1 ng/mL) statistically significantly increased the frequency of HBcAg-specific interleukin 10-secreting Treg cells. The frequency of IL7R -CD4+CD25+ cells, the expression of Toll-like receptor 2, and the suppressive function of Treg cells had declined during entecavir treatment. Conclusion. The function of HBcAg-specific T reg cells was enhanced by sHSP60 produced from HBV-infected hepatocytes. Entecavir treatment suppressed the frequency and function of T reg cells; this might contribute to the persistence of HBV infection.

Original languageEnglish
Pages (from-to)202-213
Number of pages12
JournalJournal of Infectious Diseases
Volume202
Issue number2
DOIs
Publication statusPublished - 2010 Jul 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Kondo, Y., Ueno, Y., Kobayashi, K., Kakazu, E., Shiina, M., Inoue, J., Tamai, K., Wakui, Y., Tanaka, Y., Ninomiya, M., Obara, N., Fukushima, K., Ishii, M., Kobayashi, T., Niitsuma, H., Kon, S., & Shimosegawa, T. (2010). Hepatitis B virus replication could enhance regulatory T cell activity by producing soluble heat shock protein 60 from hepatocytes. Journal of Infectious Diseases, 202(2), 202-213. https://doi.org/10.1086/653496