HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs

Peiqing Huang; Yinghong Li; Chenchang Xu; Gerry Melino; Changshun Shao; Yufang Shi

doi:10.1038/s41420-020-0262-7

HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs

Cell Death Discov. 2020 Apr 20:6:24. doi: 10.1038/s41420-020-0262-7. eCollection 2020.

Authors

Peiqing Huang¹, Yinghong Li¹, Chenchang Xu¹, Gerry Melino^{2

3}, Changshun Shao¹, Yufang Shi^{1

4

5}

Affiliations

¹ 1State Key Laboratory of Radiation Medicine and Protection, Institute for Translational Medicine, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Suzhou, China.
² 2Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy.
³ 3Medical Research Council (MRC) Toxicology Unit, University of Cambridge, Cambridge, UK.
⁴ 4The First Affiliated Hospital of Soochow University, Suzhou, China.
⁵ 5Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Abstract

Inflammatory factors such as IFNγ and TNFα could endow mesenchymal stem cells (MSCs) a potent immunomodulatory property, a process called licensing, but the mechanisms are not fully understood. We here found that glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to the active cortisol and thereby regulates tissue glucocorticoid (GC) levels, was greatly upregulated by IFNγ and TNFα in human umbilical cord-derived MSCs (UC-MSCs) in a synergistic manner. While IFNγ alone was not able to induce HSD11B1, it could increase the activity of NF-kB and thus augment the upregulation of HSD11B1 by TNFα. Interestingly, the upregulation of HSD11B1 by IFNγ and TNFα also required glucocorticoid receptor. Furthermore, HSD11B1 was shown to be required for the expression of TNF-stimulated gene 6 (TSG-6), an important anti-inflammatory effector molecule of MSCs. Therefore, the inflammatory factors IFNγ and TNFα can promote GC metabolism and thereby drive the expression of anti-inflammatory factor TSG-6 in human UC-MSCs, forming a potential negative feedback loop. These findings help to understand the relationship between inflammation and GC metabolism.

Keywords: Cytokines; Mesenchymal stem cells.