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Objectives Regulatory T cells (Tregs) mediate immunomodulation and protect against atherosclerosis. It is considered that reducing the amount of pro-inflammatory mediators could be achieved by enhancing the anti-inflammatory response, and this may be considered one of the main targets for therapy development. The inhibitory cytokines secreted by Tregs mainly include interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). Based on its known immunosuppressive involvement with other inflammatory disorders, we hypothesized that the newly characterized cytokine interleukin-37 (IL-37) might be associated with the inhibitory functions of Treg in atherosclerosis. Immune regulatory functions of IL-37 have not been completely clarified. Accordingly, we speculated that IL-37 might play a regulatory role in the immunosuppression of Tregs in atherosclerotic disease. Methods Real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to test gene expression and protein levels of IL-37 in peripheral blood and localized freshly resected arterial tissues from 84 patients with peripheral arterial occlusive disease and 50 non-atherosclerotic subjects. Results were correlated to disease hallmarks. We also evaluated the ability of recombinant IL-37 to modulate Treg cytokine secretion and T cell inhibition in relation to atherosclerotic disorder in vitro. Results: Our results revealed that IL-37 was increased in patients with chronic lower limb atherosclerotic ischemia, compared to non-atherosclerotic controls. In addition, the expression levels of circulating IL-37 correlated with disease severity of chronic lower limb ischemia. Supplementation with rIL-37 augmented levels of released IL-10 and TGF-β in supernatants of T cells co-cultured with Tregs in the enrolled patients. Conclusions: Results suggest a role for IL-37 in mediating anti-inflammatory functions in the atherosclerotic process, potentially involving enhancement of Treg inhibitory function and anti-inflammatory cytokine secretion with a particularly marked direct response in severe disease.

Background: Accumulation of myeloid-derived suppressor cells (MDSCs) constitutes a key mechanism of tumor immune evasion in gastric cancer (GC). Therefore, searching for more accurate prognostic factors affecting their immunosuppressive role has become a growing interest in cancer immunotherapy research. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice, suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-β) is responsible for the up-regulation of microRNA-494 in MDSCs. The purpose of this study was to address the effect of recombinant (rTGF-β) on the anti-inflammatory activity of MDSCs in GC and its possible association with micro-RNA-494 expression in tumor tissue. Methods: Freshly obtained GC tumor tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR-MDSCs cells from 40 GC patients and 31 corresponding controls using flow cytometry. MDSCs were co-cultured with isolated autologous T cells to assess proliferation and cytokine production in the presence and absence of rTGF-β. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-β respectively. Results: Results showed that rTGF-β markedly increased the suppressive ability of tumor MDSCs on proliferation of autologous T cells and interferon gamma production. However, no inhibitory effect was observed for MDSCs from circulation. In addition, infiltration of MDSCs in tumors is associated with the prognosis of GC. MiRNA-494 was also extensively expressed in tumor samples with a significant correlation to MDSCs. Conclusion: These results indicate that tumor-derived MDSCs but not circulatory MDSCs have an immunosuppressive effect on T cells, potentially involving TGF-β mediated stimulation. Results also suggest a role for miRNA-494 in GC progression. Therefore, control of TGF-β and miRNA-494 may be used as a treatment strategy to downregulate the immunosuppressive effect of MDSCs.

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Objectives Atherosclerosis is considered as a chronic inflammatory disorder where the central role of T cells in its pathogenesis is well known. T helper-9 cells have a distinctive effect upon the inflammatory processes. They stimulate macrophages via secretion of their cytokine interleukin-9. Based on its known involvement with other inflammatory disorders, we hypothesized that interleukin-9 might be associated with the inflammatory limb of peripheral atherosclerotic disease. Methods We tested this hypothesis on peripheral blood mononuclear cells (PBMCs) and freshly resected arterial tissues from 84 patients with peripheral arterial occlusive disease (PAOD) and 50 non-atherosclerotic subjects. A number of experimental methods were used including flow cytometry analysis of T helper-9 cells using anti-CD3, anti-CD4, and anti-interleukin-9monoclonal antibodies as well as real-time polymerase chain reaction for the assessment of gene expression of interleukin-9. In addition, circulating serum levels of interleukin-9 were measured using enzyme linked immunosorbent assay. We also evaluated the ability of recombinant interleukin-9 to modulate IL-17 release in cultured isolated CD3+ T cells with relation to atherosclerotic disorder in vitro. Results and conclusions Here we report increased percentages of T helper-9 cells and interleukin-9 levels in patients with chronic lower limb atherosclerotic ischemia, compared to healthy controls. Through investigation of different atherosclerotic patient populations with different disease stages, we found elevated interleukin-9 level both systemically and within the lesion and increased expression of cells in severe disease stages. The current study also revealed enhanced expression of mRNA levels of interleukin-9 within the atherosclerotic lesion when compared with non-atherosclerotic vessels. Levels of released IL-17 in CD3+ T cell culture supernatants supplemented with interleukin-9 were significantly positively correlated in the enrolled patients. The results suggest a role for T helper-9 cells and IL-9 in atherosclerotic process, potentially involving IL-17-mediated mechanisms. Indeed, we found that interleukin-9 promoted IL-17 release in PBMCs, with a particularly marked response in severe disease.