Our previous study indicated that interleukin (IL)-37 is involved in atherosclerosis. In the present study, Anterior tibial arteries were collected from diabetes patients and controls. A histopathological analysis showed that IL-37 was over-expressed in human atherosclerotic plaques. Many types of cells including macrophages, vascular smooth muscle cells (VSMCs), endothelial cells and T lymphocyte expressed IL-37 in human atherosclerotic plaques. ApoE−/− mice were divided into a control group and a recombinant human IL-37-treated group. The IL-37 treatment resulted in a significant decrease in macrophages and CD4+ T lymphocytes and a substantial increase in VSMCs and collagen in atherosclerotic plaques, resulting in a reduction in atherosclerotic plaque size. Furthermore, the IL-37 treatment modulated the CD4+ T lymphocyte activity, including a decrease in T helper cell type 1 (Th1) and Th17 cells and an increase in regulatory T (Treg) cells, and inhibited the maturity of dendritic cells both in vivo and in vitro. In addition, treatment with anti-IL-10 receptor monoclonal antibody abrogated the anti-atherosclerotic effects of IL-37. These data suggest that exogenous IL-37 ameliorates atherosclerosis via inducing the Treg response. IL-37 may be a novel therapeutic to prevent and treat atherosclerotic disease.Atherosclerosis is a chronic inflammatory disease in the arterial wall that is initiated mainly in response to oxidized lipoproteins and controlled by immune system 1-3 . Both innate immunity, which is antigen-and memory-independent, and adaptive immunity, which is antigen-and memory-dependent, are involved in atherosclerosis 2 . The main cell type involved in innate immunity is macrophage. In contrast, T cells and dendritic cells (DCs) are the main cell types in adaptive immunity. Regulating the immune response has been considered as the therapeutic target for the treatment of atherosclerosis 4, 5 .The novel anti-inflammatory cytokine interleukin (IL)-37 is a new member of the IL-1 family, and is only interleukin of this family that is absent in mice 6, 7 . The IL-1 family consists of 11 members, including IL-1α, IL-1β, IL-1Rα, IL-18, IL-33, IL-36Rα, IL-36α, IL-36β, IL-36γ, IL-37 and IL-38 8 . Most of the cytokines of the IL-1 family, such as IL-1 and IL-18, are pro-inflammatory cytokines and significantly promote the development of atherosclerosis 9 . Some, such as IL-1Rα and IL-33, are anti-inflammatory cytokines and efficiently ameliorate atherosclerosis in mice whereas the function of IL-36α remains unclear 9 . Evidence shows that both exogenous

Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4⁺ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.