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

Interleukin-23 (IL-23) is a pro-inflammatory cytokine initially studied in autoimmune disease which has been more recently linked to innate immunity. We observed that the expression of IL-23 is upregulated during hypoxia in hepatocyte and non-parenchymal cell (NPC) co-culture 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/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 (mRNA) during liver transplantation. Recombinant IL-23 treated hepatocytes and NPC co-culture led to IL-17, CXCL2, IFN-γ, and IRF-1 expression. With anti-IL17 and anti-Ly6G antibody neutralization, neutrophil recruitment and IFN-γ production was 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 wildtype mouse but not NKT deficient mouse. This suggests that IL-23 signaling shares a common pathway with NKT cells.

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.