Purpose: Interleukin-23 (IL-23) can activate inflammatory pathways such as CD4+ cell differentiation into IL-17 secreting Th17 cell type and increased production of IFNg leading to activation of the IRF-1 transcription factor. We have reported that hypoxia can stimulate IL-23 production in vitro, but whether IL-23 is significant during hepatic I/R is unknown. We hypothesized that using an antibody to neutralize IL-23 would protect against hepatic I/R injury through suppression of pro-inflammatory pathways.

Methods: Hepatocytes (HC), dendritic cells (DC), Kupffer cells (KC), and other non-parenchymal cells (NPC) were isolated from livers of B6 mice and were exposed to hypoxia (1% O2) or normoxia. Male Lewis rats were used for orthotopic liver transplantation (OLTx) with 18 hours of cold storage in UW solution. Animals were treated with anti-IL-23 antibody or IgG at the time of harvest (donor) and reperfusion (recipient).

Results: In vitro, DC but not HC, KC, or NPC demonstrated significantly increased IL-23 production in response to hypoxia compared to normoxia, suggesting that DC may produce IL-23 during I/R injury. In vivo, anti-IL-23 was protective against I/R injury compared to controls at 6 and 24 hours of reperfusion as measured by serum ALT and AST levels.

We have previously reported that IL-23 is increased in cold I/R injury. Total NPC were isolated from OLTx grafts at 6 hrs of reperfusion and demonstrated that treatment with anti-IL-23 resulted in significantly decreased IFNg, IL-17, and CXCL2 production compared to controls by qPCR. Also, production of the p40 subunit of IL-23 and IL-12 was decreased. Finally, livers treated with anti-IL-23 had decreased neutrophil infiltration at 24 hrs compared to controls as measured by MPO assay.

Conclusions: These data suggest that IL-23 is produced by DC in response to I/R, and contributes to damage during cold I/R in a rat OLTx model. Anti-IL-23 treatment resulted in significant protection as well as decreased production of cytokines that are known to contribute to cold I/R injury. Blocking IL-23 may represent a novel therapeutic target against hepatic I/R injury.

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