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.
Highlights
IL-33, a recently discovered cytokine that belongs to the IL-1 superfamily, activates many types of cells and induces Th2 cytokines via its transmembrane receptor, ST2L.1 IL-33 has both harmful and beneficial effects, depending on the circumstances and pathological processes involved.[2]
The low-density lipoprotein cholesterol (LDL)-c and total cholesterol (TC) levels were lower in the patients with low serum IL-33 levels (L-group) patients, whereas the high-density lipoprotein cholesterol (HDL)-c and TG levels did not differ between the groups (Table 1)
We showed that the serum IL-33 and IL-10 levels were positively correlated in coronary artery disease (CAD) patients, and those with higher serum IL-33 levels tended to have higher IL-10 concentrations
Summary
IL-33, a recently discovered cytokine that belongs to the IL-1 superfamily, activates many types of cells and induces Th2 cytokines via its transmembrane receptor, ST2L.1 IL-33 has both harmful and beneficial effects, depending on the circumstances and pathological processes involved.[2]. IL-33, a recently discovered cytokine that belongs to the IL-1 superfamily, activates many types of cells and induces Th2 cytokines via its transmembrane receptor, ST2L.1. IL-33 exerts a wide range of protective effects in the cardiovascular system. IL-33 promotes anti-oxidized low-density lipoprotein (ox-LDL) antibody production and greatly attenuates atherosclerosis in vivo.[3] an in vitro study demonstrated that IL-33 protects lipid-overloading in macrophage-derived foam cells (MFCs) via regulating the expression of genes involved in cholesterol transport, such as CD36 and ATP-binding cassette transporter A-1 (ABCA1).[4] IL-10 is an important cytokine in regulating cholesterol transport and has been shown to prevent macrophages from cholesterol overload and to stimulate cholesterol efflux.[5,6] In addition, IL-10 increases ABCA1 expression.[7,8]
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