Cross-Activating Invariant NKT Cells and Kupffer Cells Suppress Cholestatic Liver Injury in a Mouse Model of Biliary ObstructionReportar como inadecuado




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Both Kupffer cells and invariant natural killer T iNKT cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl-6 mice were injected with magnetic beads 3 days prior to bile duct ligation BDL in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression flow cytometry, mRNA expression qtPCR, nitric oxide NO. production Griess reaction, and protein secretion cytometric bead-array or ELISAs were determined. To address the potential role of NO. in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase iNOS inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen LFA-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO., and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury.



Autor: Caroline C. Duwaerts , Eric P. Sun, Chao-Wen Cheng, Nico van Rooijen, Stephen H. Gregory

Fuente: http://plos.srce.hr/



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