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Keywords:

  • Concanavalin A;
  • Hepatic inflammation;
  • CCL3/MIP-1α;
  • CD4+ T cells;
  • IFN-γ

Abstract

T cell-mediated hepatitis is associated with significant morbidity and mortality worldwide. Levels of C-C chemokine ligand 3/macrophage inflammatory protein-1α (CCL3/MIP-1α) are elevated in the serum of patients with T cell-mediated liver diseases, but its role is not fully understood. Con A-induced hepatitis is a murine liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of IFN-γ. In this study, we have used CCL3/MIP-1α gene-deficient mice to examine the role of CCL3/MIP-1α in the pathogenesis of Con A-induced hepatitis. We demonstrate a novel pro-inflammatory role for CCL3/MIP-1α since CCL3/MIP-1α deficiency significantly attenuated hepatic injury, both biochemically and histologically. Moreover, the recruitment of CCR1-expressing CD4+ T cells to the liver after Con A treatment was strikingly attenuated by CCL3/MIP-1α deficiency. Correspondingly, hepatic IFN-γ produced by the recruited CD4+ T cells was significantly reduced by CCL3/MIP-1α deficiency during Con A-induced hepatitis. Furthermore, treatment of mice with a dual CCR1/CCR5 peptide antagonist, methionylated RANTES, also markedly reduced hepatic injury and decreased the numbers of CD4+ T cells within the liver producing IFN-γ during Con A-induced hepatitis. These findings demonstrate that blockade of the CCL3/MIP-1α-CCR1 pathway may represent a novel therapeutic target for treating T cell-mediated liver diseases.