Role of CD44 in CTL-induced acute liver injury in hepatitis B virus transgenic mice.
BACKGROUND
There are many uncertain points regarding leukocyte movement in the liver, especially interaction between liver sinus endothelial cells (LSECs) and cytotoxic T lymphocytes (CTLs). We examined the role of CD44 in these interactions using the hepatitis model.


METHODS
CTLs were administered to hepatitis B virus transgenic mice (HBVTg) mice and HBVTg x CD44 knockout (KO) mice, and alanine aminotransferase activity (ALT), number of intrahepatic leukocytes, cytokines, and chemokine mRNA level were examined. To determine the number and distribution of CTLs in the liver, 5,6-carboxyfluoroscein succinimidyl ester (CFSE)-labeled CTLs was administered to HBVTg mice with or without CD44.


RESULTS
Serum ALT activity increased after 12 h, although it had declined to 4 h in the CD44KO x HBVTg mice after CTL injection. Similarly, the levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and macrophage inflammatory protein (MIP)-2 mRNAs were reduced in 4 h, although the levels were increased after 12 h in the CD44KO x HBVTg mice. The number of apoptotic hepatocytes increased intentionally at 24 h in the CD44KO x HBVTg livers, and this was thought to result from the lower activity of initial nuclear factor kappa B (NF-kappaB). Although the number of CTLs was lower at 4 h in the CD44KO x HBVTg livers, the difference of intercellular adhesion molecule (ICAM)-1 and CD86 expression on LSECs was not detected.


CONCLUSIONS
CD44 exerts and important effect on LSECs for CTL migration into the hepatocytes. However, because the CD44-deficient state exacerbated hepatic injury, attention is necessary for hepatitis treatment as CD44 target therapy.
Kimura
Kiminori
K
Division of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.
Nagaki
Masahito
M
Saio
Masanao
M
Moriwaki
Hisataka
H
Kakimi
Kazuhiro
K
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006509:Hepatitis B / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C476399:Cd44 protein, mouse; D054426:Chemokine CXCL2; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000410:Alanine Transaminase