Changes and significance of T helper-9 cells and interleukin-9 in patients with atherosclerotic chronic lower limb ischemia: Effect on IL-17 release.

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.

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