IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation.
- Author:
Hai Feng ZHANG
1
;
Mao Xiong WU
;
Yong Qing LIN
;
Shuang Lun XIE
;
Tu Cheng HUANG
;
Pin Ming LIU
;
Ru Qiong NIE
;
Qin Qi MENG
;
Nian Sang LUO
;
Yang Xin CHEN
;
Jing Feng WANG
Author Information
- Publication Type:Original Article
- MeSH: 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
- From:Experimental & Molecular Medicine 2017;49(11):e388-
- CountryRepublic of Korea
- Language:English
- 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′-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.
