Exp Mol Med.  2017 Nov;49(11):e388. 10.1038/emm.2017.183.

IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation

• Zhang HF
• Wu MX
• Lin YQ
• Xie SL
• Huang TC
• Liu PM
• Nie RQ
• Meng QQ
• Luo NS
• Chen YX
• Wang JF

• KMID: 2396793
• DOI: http://doi.org/10.1038/emm.2017.183

Abstract

We evaluated the role of IL-10- in IL-33-mediated cholesterol reduction in macrophage-derived foam cells (MFCs) and the mechanism by which IL-33 upregulates IL-10. Serum IL-33 and IL-10 levels in coronary artery disease patients were measured. The effects of IL-33 on intra-MFC cholesterol level, IL-10, ABCA1 and CD36 expression, ERK 1/2, Sp1, STAT3 and STAT4 activation, and IL-10 promoter activity were determined. Core sequences were identified using bioinformatic analysis and site-specific mutagenesis. The serum IL-33 levels positively correlated with those of IL-10. IL-33 decreased cellular cholesterol level and upregulated IL-10 and ABCA1 but had no effect on CD36 expression. siRNA-IL-10 partially abolished cellular cholesterol reduction and ABCA1 elevation by IL-33 but did not reverse the decreased CD36 levels. IL-33 increased IL-10 mRNA production but had little effect on its stability. IL-33 induced ERK 1/2 phosphorylation and increased the luciferase expression driven by the IL-10 promoter, with the highest extent within the −2000 to −1752"‰bp segment of the 5"²-flank of the transcription start site; these effects were counteracted by U0126. IL-33 activated Sp1, STAT3 and STAT4, but only the STAT3 binding site was predicted in the above segment. Site-directed mutagenesis of the predicted STAT3-binding sites (CTGCTTCCTGGCAGCAGAA→CTGCCTGGCAGCAGAA) reduced luciferase activity, and a STAT3 inhibitor blocked the regulatory effects of IL-33 on IL-10 expression. Chromatin immunoprecipitation (CHIP) confirmed the STAT3-binding sequences within the −1997 to −1700 and −1091 to −811"‰bp locus regions. IL-33 increased IL-10 expression in MFCs via activating ERK 1/2 and STAT3, which subsequently promoted IL-10 transcription and thus contributed to the beneficial effects of IL-33 on MFCs.

MeSH Terms

Binding Sites
Cholesterol
Chromatin Immunoprecipitation
Computational Biology
Coronary Artery Disease
Foam Cells*
Humans
Interleukin-10*
Interleukin-33*
Luciferases
Macrophages*
Mutagenesis, Site-Directed
Phosphorylation
RNA, Messenger
Transcription Initiation Site
Cholesterol
Interleukin-10
Interleukin-33
Luciferases
RNA, Messenger