title: Deficiency of programmed cell death 4 results in increased IL-10 expression by macrophages and thereby attenuates atherosclerosis in hyperlipidemic mice.
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.
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.|Department of Hematology, the Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.|Department of Clinical Laboratory, Provincial Hospital affiliated with Shandong University, Jinan, Shandong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Youhai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D020381:Interleukin-17; D008077:Lipoproteins, LDL; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C099252:oxidized low density lipoprotein; D016753:Interleukin-10