Modulation of liver inflammation and fibrosis by the Interleukin-1 homologue IL-37
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
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(2016) Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci U S A 113, 1411-1416
Coll-Miro, M., Francos-Quijorna, I., Santos-Nogueira, E., Torres-Espin, A., Bufler, P., Dinarello, C. A., and Lopez-Vales, R.
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(2016) Exclusive enteral nutrition in active pediatric Crohn disease: Effects on intestinal microbiota and immune regulation. J Allergy Clin Immunol 138, 592-596
Schwerd, T., Frivolt, K., Clavel, T., Lagkouvardos, I., Katona, G., Mayr, D., Uhlig, H. H., Haller, D., Koletzko, S., and Bufler, P.
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(2016) Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol 46, 1067-1081
Dinarello, C. A., Nold-Petry, C., Nold, M., Fujita, M., Li, S., Kim, S., and Bufler, P.
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(2017) IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia. J Innate Immun 9, 403-418
Schauer, A. E., Klassert, T. E., von Lachner, C., Riebold, D., Schneeweiss, A., Stock, M., Muller, M. M., Hammerschmidt, S., Bufler, P., Seifert, U., Dietert, K., Dinarello, C. A., Nold, M. F., Gruber, A. D., Nold-Petry, C. A., and Slevogt, H.
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(2018) Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int 38, 1095-1101
Grabherr, F., Grander, C., Adolph, T. E., Wieser, V., Mayr, L., Enrich, B., Macheiner, S., Sangineto, M., Reiter, A., Viveiros, A., Zoller, H., Bufler, P., Moschen, A. R., Dinarello, C. A., and Tilg, H.
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(2019) Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis. Front Immunol 10, 2632
Mountford, S., Ringleb, A., Schwaiger, R., Mayr, D., Kobold, S., Dinarello, C. A., and Bufler, P.
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(2019) Role for nuclear interleukin-37 in the suppression of innate immunity. Proc Natl Acad Sci U S A 116, 4456-4461
Li, S., Amo-Aparicio, J., Neff, C. P., Tengesdal, I. W., Azam, T., Palmer, B. E., Lopez-Vales, R., Bufler, P., and Dinarello, C. A.
