CD44-Deficient Mice Exhibit Enhanced Hepatitis After Concanavalin A Injection: Evidence for Involvement of CD44 in Activation-Induced Cell Death

Abstract

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-α, IL-2 and IFN-γ, 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.

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

“…If CD44-stimulated NKT cells are protected from the TCR-mediated AICD that typically follows lymphocyte activation, persistent NKT cell stimulation and immune dysfunction could thus follow. To contrast with this idea, a nice study by Nagarkatti and colleagues (58) showed in a model of ConA-induced hepatitis that expression of CD44 correlated with less severe disease. Furthermore, CD44 expression in that report correlated with increased AICD.…”

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…7F). These changes were reversed by treating DN32.D3 cells with the FXR 4 The online version of this article contains supplemental material. ligand 6E-CDCA (Fig.…”

“…In a second set of experiments, FXR Ϫ/Ϫ and WT mice were administered with a sublethal dose of Con A (10 mg/kg), with or without pretreatment with the same agent as described above. Mice were then sacrificed under pentothal anesthesia at 4,8,24, and 48 h after Con A administration and blood and livers were collected. Plasma aspartate aminotransferase (AST) was used as a marker of hepatic injury.…”

“…The Con A-induced hepatitis in mice is a model of T cell-mediated liver diseases (3). Following Con A administration, liver histology shows massive granulocyte accumulation, CD4 ϩ T cell infiltration, and hepatocyte necrosis/apoptosis (3,4). The induction of this hepatitis depends on CD1d-restricted invariant NKT cells, that express an invariant V␣14J␣18 TCR (5,6).…”

Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

“…The percentage of apoptotic cells was determined by evaluating z500 cells per treatment in triplicate. To confirm the results of morphologic analysis, TUNEL method was used as described elsewhere (66).…”