CCL3/MIP-1α is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4+ T cells to the liver
| Autor: | Maureen N. Ajuebor, Mark G. Swain, Amanda E. I. Proudfoot, Tai Le, Cory M. Hogaboam |
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| Rok vydání: | 2004 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male CCR1 Chemokine Receptors CCR5 T cell Immunology Receptors CCR1 Fluorescent Antibody Technique CCL3 Inflammation Interferon-gamma Mice Concanavalin A medicine Animals Immunology and Allergy Macrophage Chemokine CCL4 Receptor Chemokine CCL5 Chemokine CCL3 Mice Knockout Hepatitis biology hemic and immune systems Macrophage Inflammatory Proteins Flow Cytometry medicine.disease Disease Models Animal medicine.anatomical_structure Liver Neutrophil Infiltration biology.protein Receptors Chemokine Chemical and Drug Induced Liver Injury medicine.symptom |
| Zdroj: | European Journal of Immunology. 34:2907-2918 |
| ISSN: | 1521-4141 0014-2980 |
| DOI: | 10.1002/eji.200425071 |
| Popis: | 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-1alpha since CCL3/MIP-1alpha 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. |
| Databáze: | OpenAIRE |
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