Hepatitis B Virus Replication Could Enhance Regulatory T Cell Activity by

liver411

Producing Soluble Heat Shock Protein 60 From Hepatocytes

<http://www.journals.uchicago.edu/doi/abs/10.1086/653496>

The Journal of Infectious Diseases 2010;202:202–213
© 2010 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2010/20202-0004$15.00
DOI: 10.1086/653496

MAJOR ARTICLE
Hepatitis B Virus Replication Could Enhance Regulatory T Cell Activity by
Producing Soluble Heat Shock Protein 60 From Hepatocytes

Yasuteru Kondo,1
Yoshiyuki Ueno,1
Koju Kobayashi,2
Eiji Kakazu,1
Masaaki Shiina,1
Jun Inoue,1
Keiichi Tamai,1
Yuta Wakui,1
Yasuhito Tanaka,5
Masashi Ninomiya,1
Noriyuki Obara,1
Koji Fukushima,1
Motoyasu Ishii,3
Tomoo Kobayashi,4
Hirofumi Niitsuma,1
Satonori Kon,2 and
Tooru Shimosegawa1
1Division of Gastroenterology, Tohoku University Hospital, 2School of Health
Science, Tohoku University, 3Department of Gastroenterology, Miyagi Social
Insurance Hospital, and 4Department of Gastroenterology, Tohoku Rosai
Hospital, Sendai, and 5Clinical Molecular Informative Medicine, Nagoya City
University, Nagoya, Japan


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 ( ) and
HBeAb‐positive patients with chronic hepatitis B ( ) 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 ( ), and the levels of sHSP60 were correlated with the HBV DNA
levels ( ;  ) 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 Treg cells was enhanced by sHSP60
produced from HBV‐infected hepatocytes. Entecavir treatment suppressed the
frequency and function of Treg cells; this might contribute to the persistence
of HBV infection.


Received 14 July 2009; accepted 3 February 2010; electronically published 9
June 2010.

Reprints or correspondence: Yoshiyuki Ueno, Division of Gastroenterology,
Tohoku University Graduate School of Medicine, Seiryo 1‐1, Aobaku, Sendai,
980‐8574, Japan ([email protected]).

Potential conflicts of interest: none reported.

Financial support: Ministry of Health, Labor, and Welfare of Japan (Health and
Labor Sciences Research Grants for the Research on Measures for Intractable
Diseases); Ministry of Education, Culture, Sports, Science, and Technology of
Japan (grant 21790642 to Y.K.).



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