Hepatitis B virus replication could enhance regulatory T cell activity by producing soluble heat shock protein 60 from hepatocytes.
BACKGROUND
HBcAg-specific regulatory T (T(reg)) 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 T(reg) 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 T(reg) 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 T(reg) cells. The frequency of IL7R(-)CD4(+)CD25(+) cells, the expression of Toll-like receptor 2, and the suppressive function of T(reg) cells had declined during entecavir treatment.


CONCLUSIONS
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.
Division of Gastroenterology, Tohoku University Hospital, Tohoku University, Sendai, Japan.
Yasuteru
Y
Kondo
Yoshiyuki
Y
Ueno
Koju
K
Kobayashi
Eiji
E
Kakazu
Masaaki
M
Shiina
Jun
J
Inoue
Keiichi
K
Tamai
Yuta
Y
Wakui
Yasuhito
Y
Tanaka
Masashi
M
Ninomiya
Noriyuki
N
Obara
Koji
K
Fukushima
Motoyasu
M
Ishii
Tomoo
T
Kobayashi
Hirofumi
H
Niitsuma
Satonori
S
Kon
Tooru
T
Shimosegawa
D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology; D045744:Cell Line, Tumor; D018834:Chaperonin 60 / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D004279:DNA, Viral / Q000097:blood; D005260:Female; D005838:Genotype; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000502:physiology* / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology; D008297:Male; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology; D014162:Transfection
D000956:Antigens, Viral; D018834:Chaperonin 60; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D011994:Recombinant Proteins; D016753:Interleukin-10