IL-23 mediates murine liver transplantation ischemia-reperfusion injury via IFN-γ/IRF-1 pathway

Abstract

Interleukin-23 (IL-23) is a proinflammatory cytokine initially studied in autoimmune disease that has been more recently linked to innate immunity. We observed that the expression of IL-23 is upregulated during hypoxia in a hepatocyte and nonparen-chymal cell (NPC) coculture system, as well as during ischemia-reperfusion (I/R) injury in the liver. Interferon regulatory factor-1 (IRF-1) is a transcription factor that induces expression of multiple inflammatory cytokines and has been shown to play a critical role in liver I/R injury. We observed that IL-23 signaling induces not only the IL-17/chemokine (C-X-C motif) ligand 2 (CXCL2) pathway but also the IFN-γ/IRF-1 pathway. Quantification of cytokine genes revealed increased liver expression of IL-17a, CXCL2, and IRF-1 messenger RNA during liver transplantation. Recombinant IL-23 treated hepatocytes, and NPC coculture led to IL-17, CXCL2, IFN-γ, and IRF-1 expression. With anti-IL-17 and anti-Ly6G antibody neutralization, neutrophil recruitment and IFN-γ production were decreased during warm I/R injury. Overexpression of IL-23 in vivo through use of an adenovirus vector also led to expression of IL-17, CXCL2, IFN-γ, and IRF-1. The increased expression of IL-23 also led to increased apoptosis in the liver. By neutralization of IL-23 through use of an anti-IL-23p19 antibody, we were able to attenuate liver damage in a wild-type but not a natural killer T (NKT) cell-deficient mouse. This suggests that IL-23 signaling shares a common pathway with NKT cells. In conclusion, IL-23 is induced early by I/R in the liver. Its signaling leads to activation of the IL-17/CXCL2 and IFN-γ/IRF-1 pathways, resulting in increased apoptosis and necrosis. NEW & NOTEWORTHY IL-23 is expressed early during cold ischemia-reperfusion (I/R), and this expression is associated with expression of IL-17 and chemokine (C-X-C motif) ligand 2. Neutralization of IL-23 during cold I/R can significantly reduce liver damage as well as decrease cytokine production and neutrophil infiltration in the liver. IL-23 appears to activate IFN-γ production in natural killer T cells within the liver which, in turn, activates interferon regulatory factor-1, a known inflammatory transcription factor during I/R injury.