Beneficial effects of IL-1 cytokine inactivation and the role of the serine/threonine kinase MK-2 in hepatic steatosis in a murine obesity model

Background and Aims:

Although non-alcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease worldwide, its pathogenesis is yet poorly understood. Recent studies show that the pro-inflammatory cytokines IL-1αand IL-1β play a crucial role in disease development. Their recognition by cells does not only result in transcriptional regulation of many IL-1 target genes, but also negatively affects cell surface expression of the IL-6 signal transducer gp130 in an MK-2 (mitogen-activated protein kinase-activated protein kinase 2)-dependent mechanism. Therefore the cells might become less susceptible to IL-6 signalling, which is suspected to have a beneficial effect in steatosis. We aim to investigate the role of IL-1 in early steatosis in IL-1-immunized and MK-2 deficient mice.

Methods:

C57BL/6J wild-type and MK-2 deficient mice were fed a Surwit High Fat Diet (HFD) for 8 weeks. For inactivation of IL-1, mice were subcutaneously vaccinated against IL-1α/β using virus-like particles presenting antigens of IL-1 α or β (Cytos Biotechnology) on their surfaces before HFD feeding. Robust anti-IL-1α and anti-IL-1β auto-antibody responses were assessed by ELISA. Liver and fat tissue was analysed and RNA was isolated to assess gene expression via qPCR.

Results:

Our recent findings show that inactivation of IL-1 by vaccination with virus-like particles strikingly reduces steatosis in mice fed a HFD for 6 weeks on a macroscopic and molecular level. Lipid accumulation is drastically reduced and lipogenic enzyme as well as pro-inflammatory molecule expression is significantly downregulated in hepatic tissue. Although no cytokine expression is detectable in the liver at such an early time-point, inflammation and leukocyte infiltration is evident in adipose tissue. IL-1β serum levels show no differences between chow- or HFD-fed mice, pointing towards an indirect effect of fatty tissue inflammation on the liver. MK-2 deficient mice show no significant differences in liver weight or expression of any inflammatory markers in qPCR after 8 weeks of feeding.

Conclusion:

Our results strongly support future studies on IL-1 for clinical applications since its inactivation effectively prevents liver steatosis in HFD-fed mice. The present study indicates that the main initial target site for IL-1 is the adipose tissue rather than the liver itself. Therefore, the effect on the liver appears to be indirect as IL-1β serum levels do not increase upon feeding mice a HFD. Furthermore, MK-2 deficient mice fed either standard chow or HFD for eight weeks show no difference in liver or adipose tissue inflammation, indicating that the IL-1/IL-6 cross-talk does not affect the early phase of steatosis.

Corresponding author: Wohlfahrt, Julia

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