CCL3/MIP-1α is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4+ T cells to the liver

被引:70
作者
Ajuebor, MN
Hogaboam, CM
Le, T
Proudfoot, AEI
Swain, MG
机构
[1] Univ Calgary, Dept Med, Fac Med, Gastrointestinal Res Grp,Liver Unit, Calgary, AB T2N 4N1, Canada
[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA
[3] Serono Pharmaceut Res Inst, Geneva, Switzerland
关键词
concanavalin A; hepatic inflammation; CCL3/MIP-1; alpha; CD4(+) T cells; IFN-gamma;
D O I
10.1002/eji.200425071
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
T cell-mediated hepatitis is associated with significant morbidity and mortality worldwide. Levels of C-C chemokine ligand 3/macrophage inflammatory protein-1alpha (CCL3/MIP-1alpha) 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-gamma. In this study, we have used CCL3/MIP-1alpha. gene-deficient mice to examine the role of CCL3/MIP-1alpha. in the pathogenesis of Con A-induced hepatitis. We demonstrate a novel pro-inflammatory role for CCL3/MIP-1a since CCL3/MIP-1a 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-1alpha deficiency. Correspondingly, hepatic IFN-gamma produced by the recruited CD4(+) T cells was significantly reduced by CCL3/MIP-1alpha 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-gamma during Con A-induced hepatitis. These findings demonstrate that blockade of the CCL3/MIP-1alpha-CCR1 pathway may represent a novel therapeutic target for treating T cell-mediated liver diseases.
引用
收藏
页码:2907 / 2918
页数:12
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