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

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Abstract

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.

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Author information

Authors and Affiliations

  1. Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, 68 Changle Rd, Nanjing, 210006, Jiangsu, China

    Zhang Qian, Chen Chen & Liu Chao

  2. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China

    Feng Shaofang

  3. Medical Department, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China

    Shi Chunhua

  4. Jinling Hospital, Medical School of Nanjing University, 22 Hankou Rd, Nanjing, 210093, Jiangsu, China

    Wang Nan

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Contributions

Zhang Qian conceived, designed and performed the experiments, analyzed data, wrote and revised the manuscript. Feng Shaofang and Shi chunhua conducted the research and analyzed the data. Chen Chen helped us revise the manuscript. Wang Nan and Liu Chao conceived, supervised, funded, and reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wang Nan or Liu Chao.

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Supplementary Information

Fig. S1

Determination of the concentrations of TNF-α and IL-33 in HUVEC. (A) VCAM-1 expression in HUVEC after a gradient periods of TNF-α exposure. (B) VCAM-1 expression in HUVEC treated with different concentrations of IL-33 (with or without 10 ng/mL TNF-α). Notes: Data represented mean ± SD; n = 3; **P < 0.01. Abbreviations: IL, interleukin; VCAM-1, vascular cell adhesion molecule-1; TNF, tumor necrosis factor; HUVEC, human umbilical vein endothelial cells (PNG 422 kb)

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Qian, Z., Shaofang, F., Chen, C. et al. IL-33 Suppresses the Progression of Atherosclerosis via the ERK1/2-IRF1-VCAM-1 Pathway. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07523-3

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