IL-37 - a regulation relevant cytokine in liver regeneration?

Background Despite numerous advances in liver surgery one of the limiting factors is the functional capacity of the future-liver-remnant. Enhancing the regenerative capacity is crucial for expanding indications for hepatic resections (HR). This could either be done by augmentation, but new advances in optimizing the liver for eg. extended resections could be of high interest. Interleukin-37 (IL-37) is widely expressed in the liver, exerts anti-inflammatory effects in hepatic diseases and reduces liver injury induced by ischemia-reperfusion-injury. However, the impact of IL-37 on liver regeneration (LR) is unknown. Endpoints consisted of: i) defining the role of IL-37 in the regulation of LR following liver resection; ii) elucidating the mechanistic context of IL-37 and LR by using a model of 2/3 partial hepatectomy (PH); iii) characterizing the metabolic profile of murine LR and identifying IL-37 as regeneration relevant cytokine that regulates LR via metabolic pathways.

Methods Serum levels of IL-37 were assessed in 52 patients undergoing HR. Evaluation of LR after PH in transgenic (IL-37tg) mice and wild-type (WT) controls. Serum samples of both genotypes were analyzed in a targeted metabolomic approach covering 630 different compounds.

Results An upregulation of IL-37 was noticed during hepatic resection and especially in major resections and primary liver tumours. In mice, IL-37 increased cell proliferation during LR 48 hours post PH (BrdU, PCNA, liver-to-body-weight-ratio). Interestingly, only 5 significant regulating metabolites were identified, either dependent on genotype and time and/or the interaction of these two factors. These were namely 5-AVA, alpha-AAA, phenylalanine and the sum of indoles.

Conclusion IL-37 is a regulation relevant cytokine in the liver by using a metabolomic pathway (eg. production of 5-AVA). This is an interesting finding which should be worked up and may be implemented in clinical studies.

Publication History

Article published online:
01 September 2021