Modulation of liver inflammation and fibrosis by the Interleukin-1 homologue IL-37

• Applicant: Professor Dr. Philip Clemens Reinhard Bufler
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 288401774

Sustained inflammation is a common characteristic of chronic liver injury and induces the development of liver fibrosis, cirrhosis and potentially liver cancer. Liver Kupffer cells are key modulators of hepatic stellate cell function by secretion of immunologically active proteins such as TGFbeta. TGFbeta is a cytokine with anti-inflammatory properties and promotes liver fibrosis via the activation of Sma- and Mad-related protein 3 (Smad3). We reported that IL-37, a novel cytokine of the interleukin-1 family, interacts with Smad3. After cell stimulation IL 37 translocates to the nucleus, possibly in concert with Smad3 to regulate transcriptional activity. The inflammatory response to lipopolysaccharide in IL-37-transgenic mice was increased when endogenous Smad3 was depleted indicating a functional cooperation of both proteins. IL-37 is also secreted in the supernatant of stimulated cells. Extracellular IL-37 is active by binding to the IL18Ra and recruitment of anti-inflammatory single receptor Ig-like receptor SIGIRR. In summary, IL-37 appears to be a unique cytokine of the IL-1 family through its ability to interfere with the signaling cascade of TGFbeta in order to modulate inflammation. IL-37 is expressed in human hepatocyte and bile duct epithelia. We demonstrated that isolated hepatic Kupffer cells from IL-37tg mice have a markedly reduced inflammatory response to LPS in comparison to wild-type Kupffer cells. Others showed that recombinant IL-37 inhibits Kupffer cell activity and ischemia-induced liver damage in mice. We propose that IL-37 modulates liver inflammation and subsequent fibrogenesis by downregulation of IL-1b- and interaction with TGFbeta-dependent pathways. The results of this research proposal will show whether targeting IL-37 could be a useful therapeutic strategy in inflammatory and fibrogenic liver diseases.

• DFG Programme: Research Grants