Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions

The, Erlinda; Zhai, Yufeng; Yao, Qingzhou; Ao, Lihua; Li, Suzhao; Fullerton, David A.; Dinarello, Charles A.; Meng, Xianzhong

doi:10.7150/ijbs.85745

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Theranostics

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Int J Biol Sci 2023; 19(12):3908-3919. doi:10.7150/ijbs.85745 This issue Cite

Research Paper

Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions

Erlinda The, Yufeng Zhai, Qingzhou Yao, Lihua Ao, Suzhao Li, David A. Fullerton, Charles A. Dinarello, Xianzhong Meng^✉

Departments of Surgery and Medicine, University of Colorado Denver, Aurora, CO 80045.

Citation:

The E, Zhai Y, Yao Q, Ao L, Li S, Fullerton DA, Dinarello CA, Meng X. Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions. Int J Biol Sci 2023; 19(12):3908-3919. doi:10.7150/ijbs.85745. https://www.ijbs.com/v19p3908.htm

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Abstract

Calcific aortic valve disease (CAVD) is a chronic inflammatory disease with slow progression that involves soluble extracellular matrix (ECM) proteins. Previously, we found that recombinant interleukin (IL)-37 suppresses aortic valve interstitial cells (AVIC) inflammatory response through the interaction with IL-18 receptor α-chain (IL-18Rα) on the cell surface. Endogenous IL-37 can be retained in the cytoplasm or released into extracellular spaces. It remains unknown whether recombinant IL-37 exerts the anti-inflammatory effect through intracellular action. Here, we found that recombinant IL-37 suppressed AVIC inflammatory response to soluble ECM proteins. Interestingly, recombinant IL-37 was internalized by human AVICs in an IL-18Rα-independent fashion. Blocking endocytic pathways reduced the internalization and anti-inflammatory potency of recombinant IL-37. Overexpression of IL-37 in human AVICs suppressed soluble ECM proteins-induced NF-κB activation and the production of ICAM-1 and VCAM-1. However, IL-37D20A (mutant IL-37 lacking nucleus-targeting sequences) overexpression had no such effect, and the inflammatory response to soluble ECM proteins was essentially intact in AVICs from transgenic mice expressing IL-37D20A. Together, recombinant IL-37 can be internalized by human AVICs through endocytosis. Intracellular IL-37 exerts an anti-inflammatory effect through a nucleus-targeting mechanism. This study highlights the potent anti-inflammatory effect of recombinant IL-37 in both extracellular and intracellular compartments through distinct mechanisms.

Keywords: aortic valve, endocytic pathway, IL-37, inflammation, nuclear action

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APA

The, E., Zhai, Y., Yao, Q., Ao, L., Li, S., Fullerton, D.A., Dinarello, C.A., Meng, X. (2023). Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions. International Journal of Biological Sciences, 19(12), 3908-3919. https://doi.org/10.7150/ijbs.85745.

ACS

The, E.; Zhai, Y.; Yao, Q.; Ao, L.; Li, S.; Fullerton, D.A.; Dinarello, C.A.; Meng, X. Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions. Int. J. Biol. Sci. 2023, 19 (12), 3908-3919. DOI: 10.7150/ijbs.85745.

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CSE

The E, Zhai Y, Yao Q, Ao L, Li S, Fullerton DA, Dinarello CA, Meng X. 2023. Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions. Int J Biol Sci. 19(12):3908-3919.

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