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Effect of Homocysteine on the Differentiation of CD4(+) T Cells into Th17 Cells

机译：同型半胱氨酸对CD4（+）T细胞分化为Th17细胞的影响

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BackgroundThe hyperhomocysteinaemia (Hhcy) is a common phenomenon observed in patients with inflammatory bowel disease (IBD). Our previous study showed that Hhcy aggravated intestinal inflammation in an animal model of colitis. Increased levels of IL-17 and RORt were also observed in this animal model of colitis with Hhcy. However, the direct effect of homocysteine on the differentiation of Th17 cells has never been studied. The aim of this study was to investigate the direct effect of Hhcy on the differentiation of CD4(+) T cells into Th17 cells.MethodLamina propria lymphocytes (LPLs) in colonic mucosa of Wistar rats were isolated and cultured under Th17-inducing (iTH17) environments. Different concentrations of the Hcy (0-100mol/ml) were added alone or combined with IL-23 (100ng/ml) or folate (5mol/ml). The LPLs were divided into eight groups as follows: (1) Control group; (2) 10mol/ml Hcy group; (3) 25mol/ml Hcy group; (4) 50mol/ml Hcy group; (5) 100mol/ml Hcy group; (6) 100ng/ml IL-23 group; (7) 50mol/ml Hcy+100ng/ml IL-23 group and (8) 50mol/ml Hcy+100ng/ml IL-23+5mol/ml folate group. The protein expression levels of IL-17, retinoid-related orphan nuclear receptor-t (RORt), p38 MAPK, phosphorylated p38 MAPK, cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 and cyclooxygenase 2 (COX2) were detected by immunoblot analysis. The protein level of prostaglandin E2 (PGE2) and IL-17 was detected by ELISA, and IL-17 and RORt-positive CD4(+) T cells were stained and analyzed by flow cytometry.ResultsHcy increased the protein levels of IL-17, RORt, the ratio of phosphorylated p38 MAPK to p38 MAPK (p-p38/p38), the ratio of phosphorylated cPLA2 to cPLA2 (p-cPLA2/cPLA2) and COX2. The effect was concentration dependent to a certain degree; Hcy of 50mol/ml was the optimal concentration to increase the protein levels of those molecules. The level of IL-17 and PGE2 in the cell culture supernatants and the expression of IL-17 and RORt in positive CD4(+) T cells were also increased in the group of Hhcy. IL-23 showed a cooperative effect with Hcy on the differentiation of CD4(+) Th cells into Th17 cells, whereas folate supplementation showed an inhibition action.ConclusionsHomocysteine promoted the differentiation of CD4(+) T cells into Th17 cells in a dose-dependant manner. This effect could be inhibited by folate.
机译：背景技术Hyperhomysteina血症（HHCy）是炎症性肠病（IBD）患者观察到的常见现象。我们以前的研究表明，Hhcy在结肠炎的动物模型中加剧了肠道炎症。在这种结肠炎的血小性与hhcy的动物模型中也观察到IL-17和ROR的水平增加。然而，从未研究过同型半胱氨酸对Th17细胞分化的直接影响。本研究的目的是探讨HHCY对CD4（+）T细胞分化为TH17细胞的直接效果。在TH17诱导下分离出幼虫大鼠粘膜粘膜粘膜卟啉肽（LPLS），并在Th17诱导下培养（ith17）环境。单独添加不同浓度的HCY（0-100mol / mL）或与IL-23（100ng / ml）或叶酸（5mol / ml）组合。 LPLS分为八组，如下：（1）对照组; （2）10mol / ml Hcy组; （3）25mol / ml Hcy组; （4）50mol / ml Hcy组; （5）100mol / ml Hcy组; （6）100ng / ml IL-23组; （7）50mol / ml Hcy + 100ng / ml IL-23基团和（8）50mol / ml Hcy + 100ng / ml IL-23 + 5mol / ml叶酸组。通过免疫印迹分析检测IL-17，类含有含有孤儿核受体-T（ROROR），P38 MAPK，磷酸化P38MAPK，胞质磷脂素酶A2（CPLA2），磷酸化-CPLA2和环氧化酶2（COX2）的蛋白质表达水平。通过ELISA检测前列腺素E2（PGE2）和IL-17的蛋白质水平，并通过流式细胞术染色IL-17和ROTOR阳性CD4（+）T细胞并分析IL-17的蛋白质水平增加， ROROR，磷酸化的P38 MAPK与P38 MAPK（P-P38 / P38）的比率，磷酸化CPLA2与CPLA2（P-CPLA2 / CPLA2）和COX2的比率。效果浓度依赖于一定程度; 50mol / ml的Hcy是增加这些分子的蛋白质水平的最佳浓度。在HHCE组中，细胞培养上清液中IL-17和PGE2的水平和IL-17的表达和阳性CD4（+）T细胞的表达也增加。 IL-23显示了Hcy对CD4（+）TH细胞分化为Th17细胞的协同效果，而叶酸补充表明抑制作用。结合卤代细胞酮促进CD4（+）T细胞在剂量依赖性中将CD4（+）T细胞分化为TH17细胞方式。这种效果可以通过叶酸抑制。

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