Critical role of CD44 in hepatotoxin-mediated liver injury.
OBJECTIVE
Blocking of adhesion molecules is considered to be one of the therapeutic strategies inflammatory diseases, although it remains unclear whether this strategy is beneficial.


METHODS
We used CD44-deficient mice to assess whether inhibition of CD44 could control liver injury caused by carbon tetrachloride (CCl(4)).


RESULTS
CD44-deficient mice exhibited suppressed liver inflammation during the early phase (within 6h) after CCl(4) injection due to reduced inflammatory cell infiltration and cytokine production, but showed severe liver inflammation with increased numbers of apoptotic hepatocytes at the late phase (after 12h). The induction of hepatocyte apoptosis was triggered by reduced NF-kappaB activity, which was induced by the low inflammatory cytokine concentrations. Furthermore, macrophages contributed to the induction of hepatocyte apoptosis, since neutralization by an anti-CD11b antibody significantly protected against hepatocyte apoptosis. Finally, we found that blocking of MIP-2 and TNF-alpha reduced hepatocyte apoptosis with decreased numbers of intrahepatic leukocytes and reduced inflammatory cytokine production.


CONCLUSIONS
These findings suggest that targeting of CD44 as a therapeutic approach for inflammatory liver diseases may require caution for particular immune systems in the liver.
Kimura
Kiminori
K
Department of Immunotherapeutics (Medinet), Graduate School of Medicine, The University of Tokyo, 1-3-7 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kkimura@m.u-tokyo.ac.jp
Nagaki
Masahito
M
Kakimi
Kazuhiro
K
Saio
Masanao
M
Saeki
Tomomi
T
Okuda
Yumiko
Y
Kuwata
Kazuo
K
Moriwaki
Hisataka
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D054426:Chemokine CXCL2 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007107:Immune System / Q000276:immunology* / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C476399:Cd44 protein, mouse; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride