CD44-deficient mice exhibit enhanced hepatitis after concanavalin a injection: Evidence for involvement of CD44 in activation-induced cell death

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 inv estigated the role of CD44 in Con A-induced hepatitis. Intravenous administ ration 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. A dministration of lower doses of Con A (12 mg/kg body weight) into CD44 WT m ice induced hepatitis as evident from increased plasma aspartate aminotrans ferase levels accompanied by active infiltration of mononuclear cells and n eutrophils, and significant induction of apoptosis in the liver. Interestin gly, CD44 KO mice injected with similar doses of Con A exhibited more sever e acute suppurative hepatitis. Transfer of spleen cells from Con A-injected CD44 KO mice into CD44 WT mice induced higher levels of hepatitis when com pared with transfer of similar cells from CD44 WT mice into CD44 WT mice. T he increased hepatitis seen in CD44 KO mice was accompanied by increased pr oduction of cytokines such as TNF-alpha, IL-2 and IFN-gamma, but not Fas or Fas ligand. The increased susceptibility of CD44 KO mice to hepatitis corr elated with the observation that T cells from CD44 KO mice were more resist ant to activation-induced cell death when compared with the CD44 WT mice. T ogether, these data demonstrate that activated T cells use CD44 to undergo apoptosis, and dysregulation in this pathway could lead to increased pathog enesis in a number of diseases, including hepatitis.