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*
Departments of Microbiology and Immunology and Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298;
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061; and
Department of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario, Canada
Administration of Con A induces severe injury to hepatocytes in
mice and is considered to be a model for human hepatitis. In the
current study, we investigated the role of CD44 in Con A-induced
hepatitis. Intravenous administration of Con A (20 mg/kg) caused 100%
mortality in C57BL/6 CD44-knockout (KO) mice, although it was not
lethal in C57BL/6 CD44 wild-type (WT) mice. Administration of lower
doses of Con A (12 mg/kg body weight) into CD44 WT mice induced
hepatitis as evident from increased plasma aspartate aminotransferase
levels accompanied by active infiltration of mononuclear cells and
neutrophils, and significant induction of apoptosis in the liver.
Interestingly, CD44 KO mice injected with similar doses of Con A
exhibited more severe acute suppurative hepatitis. Transfer of spleen
cells from Con A-injected CD44 KO mice into CD44 WT mice induced higher
levels of hepatitis when compared with transfer of similar cells from
CD44 WT mice into CD44 WT mice. The increased hepatitis seen in CD44 KO
mice was accompanied by increased production of cytokines such as
TNF-
, IL-2 and IFN-
, but not Fas or Fas ligand. The increased
susceptibility of CD44 KO mice to hepatitis correlated with the
observation that T cells from CD44 KO mice were more resistant to
activation-induced cell death when compared with the CD44 WT mice.
Together, these data demonstrate that activated T cells use CD44 to
undergo apoptosis, and dysregulation in this pathway could lead to
increased pathogenesis in a number of diseases, including
hepatitis.
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