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Deficiency of programmed cell death 4 results in increased IL-10 expression by macrophages and thereby attenuates atherosclerosis in hyperlipidemic mice

Cellular & Molecular Immunology volume 13, pages 524–534 (2016)Cite this article

Abstract

Programmed cell death 4 (Pdcd4) is a newly defined inhibitor of transcription and translation and a tumor suppressor. Recent studies have suggested that Pdcd4 may also be involved in some inflammatory diseases. However, its role in atherosclerosis, a chronic inflammation of the arterial wall, remains to be investigated. Here, we found that Pdcd4 deficiency in mice increased the expression of IL-10 in macrophages and decreased the expression of IL-17 in T cells in the presence of an atherosclerosis-associated stimulator in vitro and in high fat-induced atherosclerotic plaques. Importantly, knocking out Pdcd4 led to a decrease in atherosclerotic lesions in Apoe−/− mice fed a high fat diet. This effect could be partly reversed by blocking IL-10 with a neutralizing antibody but not by the application of exogenous IL-17. Further mechanistic studies revealed that Pdcd4 negatively regulated the expression of IL-10 in an ERK1/2- and p38-dependent manner. These results demonstrate that Pdcd4 deficiency attenuates atherosclerosis in hyperlipidemic mice in part through the upregulation of the anti-inflammatory cytokine IL-10. This indicates that endogenous Pdcd4 promotes atherosclerosis and therefore represents a potential therapeutic target for patients with atherosclerosis.

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Acknowledgements

We are grateful to the Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University for expert technical assistance. This work was supported by the National 973 Basic Research Program of China (Nos. 2011CB503906, 2012CB518603), grants from the National Natural Science Foundation of China (81172863, 31470856 and 91439124) and the Natural Science Foundation of Shandong (Z2008C02), and a grant from the China Postdoctoral Science Foundation (2014 M551912).

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Author notes

  1. Yang Jiang and Qi Gao: These authors contributed equally to this work.

  2. Dr L Zhang, Department of Immunology, School of Medicine, Shandong University, 44# Wen Hua Western Road, Jinan, Shandong, 250012, China E-mail: zhanglining@sdu.edu.cn

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China

    Yang Jiang, Qi Gao, Liyang Wang, Chun Guo, Faliang Zhu, Bo Wang, Qun Wang & Lining Zhang

  2. Department of Hematology, the Second Hospital of Shandong University, Jinan, Shandong, China

    Yang Jiang

  3. Department of Clinical Laboratory, Provincial Hospital affiliated with Shandong University, Jinan, Shandong, China

    Qi Gao

  4. The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong, China

    Fei Gao

  5. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Youhai Chen

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Jiang, Y., Gao, Q., Wang, L. et al. Deficiency of programmed cell death 4 results in increased IL-10 expression by macrophages and thereby attenuates atherosclerosis in hyperlipidemic mice. Cell Mol Immunol 13, 524–534 (2016). https://doi.org/10.1038/cmi.2015.47

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