C-C chemokine ligand 2/monocyte chemoattractant protein-1 directly inhibits NKT cell IL-4 production and is hepatoprotective in T cell-mediated hepatitis in the mouse.
T cell-mediated liver diseases are associated with elevated serum levels of C-C chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). However, the extent to which the actions of CCL2/MCP-1 contribute to the pathogenesis of T cell-mediated hepatitis remains incompletely understood. Con A-induced hepatitis is a liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of TNF-alpha, IFN-gamma, and IL-4. The present study examined the role of CCL2/MCP-1 in the pathogenesis of T cell-mediated hepatitis induced by Con A administration in the mouse. We demonstrate a novel hepatoprotective role for CCL2/MCP-1 during Con A-induced hepatitis, because CCL2/MCP-1 neutralization strikingly enhanced hepatic injury, both biochemically and histologically, after Con A administration. Furthermore, CCL2/MCP-1 neutralization was associated with a significant reduction in the hepatic levels of TNF-alpha and IFN-gamma, but with a significant increase in hepatic IL-4 levels. Moreover, IL-4 production and CCR2 expression by Con A-stimulated CD3(+)NK1.1(+) T cells was significantly reduced by rMCP-1 treatment in vitro. In summary, we propose that CCL2/MCP-1 fulfills a novel anti-inflammatory role in T cell-mediated hepatitis by inhibiting CD3(+)NK1.1(+) T cell-derived IL-4 production through direct stimulation of its specific receptor CCR2. These findings may have direct clinical relevance to T cell-mediated hepatitis.
Liver Unit, Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Maureen N
MN
Ajuebor
Cory M
CM
Hogaboam
Tai
T
Le
Mark G
MG
Swain
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007106:Immune Sera / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D007106:Immune Sera; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D003208:Concanavalin A; D015847:Interleukin-4