IL-33 Suppresses the Progression of Atherosclerosis via the ERK1/2-IRF1-VCAM-1 Pathway

Purpose This study was designed to explore the effects of interleukin 33 ( IL-33) on the progression of atherosclerosis and the possible mechanism. Methods The adhesion assay was performed on isolated peripheral blood mononuclear cells ( PBMCs) and human umbilical vein endothelial cells (HUVEC) . The expression of proteins and messenger RNA ( mRNA ) were detected by western blot and quantitative real-time polymerase chain reaction ( PCR ), including intercellular cell adhesion molecule-1 ( ICAM-1) , vascular cell adhesion molecule-1 ( VCAM-1) , and P-selectin . The effect of IL-33 on the interaction of growth stimulation expressed gene 2 ( ST2) with myeloid differentiation factor 88 ( MyD88) and interleukin-1 receptor-associated kinase (IRAK) 1/4 were investigated using co-immunoprecipitation assay. An apolipoprotein ( Apo ) E -/- mice model was used to confirm the effect of IL-33 on atherosclerosis progression. Area of plaques was recorded by hematoxylin-eosin ( H&E ) staining. The severity of atherosclerosis plaque was evaluated using immunohistochemistry assay, and lipid accumulation was measured by an oil red O staining. In contrast, western blot was performed to detect the expression levels of VCAM-1, extracellular signal-regulated kinase ( ERK ) 1/2, and interferon regulatory factor 1 ( IRF1) . Results Our study observed that IL-33 suppressed cell adhesion and the expression of VCAM-1 in tumor necrosis factor-α ( TNF-α ) exposed HUVEC. Moreover, the addition of IL-33 significantly inhibited the expression of IRF1 and the binding level of IRF1 to VCAM-1 and also promoted the phosphorylation level of IRAK1/4 and ERK1/2 compared to TNF-α-stimulated HUVEC. The ST2 neutralizing antibody or ERK pathway inhibitor SCH772984 reversed the regulatory effects of IL-33 on HUVEC, suggesting that IL-33 suppressed IRF1 and VCAM-1 dependent on binding to ST2 and activating the ERK1/2 signaling pathway. Further investigation in vivo confirmed that IL-33 decreased the expressions of IRF1 and VCAM-1 by activating the phosphorylation of ERK1/2 in the thoracic aorta of Apo E -/- mice. Conclusion In conclusion, our results demonstrated that IL-33 plays a protective role in the progression of atherosclerosis by inhibiting cell adhesion via the ERK1/2-IRF1-VCAM-1 pathway. This study may provide a potential therapeutic way to prevent the development of atherosclerosis.