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

• Final Report Year: 2020

Final Report Abstract

Chronic inflammation is an important trigger of liver fibrogenesis. Although well described, inflammatory pathways have received little attention as therapeutic targets for chronic liver diseases. IL-37 has proven to exert broad-spectrum anti-inflammatory effects in vitro and in vivo. Furthermore, IL-37 interferes with the TGF-β signaling pathway by interaction with Smad3. Since TGF-β is a core cytokine involved in liver fibrogenesis we hypothesized that IL-37 modulates liver fibrosis by functional interaction with the TGF-β signaling pathway. Here we show that transgene expression of IL-37 in mice is associated with prolonged survival, reduced hepatic damage and early fibrosis markers as well as less histologically proven liver fibrosis after bile duct ligation (BDL). IL-37tg mice were also protected against CCl4-induced liver inflammation. In addition, colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout mice expressing IL-37. Spontaneous as well as LPS/TGF-β-induced cytokine release and pro-fibrogenic gene expression was lower in hepatic stellate and Kupffer cells isolated from IL- 37tg mice and IL-37 overexpressing, IL-1β- or LPS-stimulated human LX-2 stellate, RAW264.7 and A549 cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, in LX2 cells or murine HSCs. We therefore conclude that predominantly intracellular IL-37 down-regulates pathways of liver inflammation and fibrosis. In addition to our functional studies we show that IL-37 expression is increased in pediatric autoinflammatory liver diseases and correlates with fibrosis, serum transaminases, alkaline phosphatase and IgG. In addition, we demonstrate in a large cohort of adults with chronic liver diseases elevated serum IL-37 levels correlating with clinical markers of liver fibrosis. In summary, our results indicate that IL-37 may represent a novel target to modulate the clinical course of chronic liver diseases.

Publications

• (2016) Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci U S A 113, 1411-1416
  Coll-Miró, Marina; Francos-Quijorna, Isaac; Santos-Nogueira, Eva; Torres-Espin, Abel; Bufler, Philip; Dinarello, Charles A. & López-Vales, Rubèn
  
• (2016) Exclusive enteral nutrition in active pediatric Crohn disease: Effects on intestinal microbiota and immune regulation. J Allergy Clin Immunol 138, 592-596
  Schwerd, Tobias; Frivolt, Klara; Clavel, Thomas; Lagkouvardos, Ilias; Katona, Gabor; Mayr, Doris; Uhlig, Holm H.; Haller, Dirk; Koletzko, Sibylle & Bufler, Philip
  
• (2016) Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol 46, 1067-1081
  Dinarello, Charles A.; Nold‐Petry, Claudia; Nold, Marcel; Fujita, Mayumi; Li, Suzhao; Kim, Soohyun & Bufler, Philip
  
• (2017) IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia. J Innate Immun 9, 403-418
  Schauer, Anja E.; Klassert, Tilman E.; von Lachner, Carolin; Riebold, Diana; Schneeweiß, Anne; Stock, Magdalena; Müller, Mario M.; Hammerschmidt, Sven; Bufler, Philip; Seifert, Ulrike; Dietert, Kristina; Dinarello, Charles A.; Nold, Marcel F.; Gruber, Achim D.; Nold-Petry, Claudia A. & Slevogt, Hortense
  
• (2018) Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int 38, 1095-1101
  Grabherr, Felix; Grander, Christoph; Adolph, Timon E.; Wieser, Verena; Mayr, Lisa; Enrich, Barbara; Macheiner, Sophie; Sangineto, Moris; Reiter, Andreas; Viveiros, Andre; Zoller, Heinz; Bufler, Philip; Moschen, Alexander R.; Dinarello, Charles A. & Tilg, Herbert
  
• (2019) Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis. Front Immunol 10, 2632
  Mountford, Steffeni; Ringleb, Andrea; Schwaiger, Rahel; Mayr, Doris; Kobold, Sebastian; Dinarello, Charles A. & Bufler, Philip
  
• (2019) Role for nuclear interleukin-37 in the suppression of innate immunity. Proc Natl Acad Sci U S A 116, 4456-4461
  Li, Suzhao; Amo-Aparicio, Jesus; Neff, Charles P.; Tengesdal, Isak W.; Azam, Tania; Palmer, Brent E.; López-Vales, Rubèn; Bufler, Philip & Dinarello, Charles A.