雌二醇通过抑制JAK/STAT介导的炎症反应并重塑T细胞表型促进复发性外阴阴道念珠菌病的发病OA
Estradiol promotes the pathogenesis of recurrent vulvovaginal candidiasis by suppressing jak/stat-mediated inflammation and remodeling T cell phenotypes
目的 探讨雌二醇(E2)对上皮细胞炎症因子(IL-17/IL-36家族)表达、T细胞JAK/STAT通路磷酸化及表型分化的影响.方法 分别构建人阴道上皮细胞(VK2/E6E7)和人CD4+初始T淋巴细胞白念珠菌(C.albicans)感染模型,两个模型均分为空白组、E2组(加入10-8 mol/L E2)、C.albicans组(加入 1 × 106 cfu/mL C.albicans)和 C.albicans+E2 组(同时含 10-8 mol/L E2 和 1 × 106 cfu/mL C.albi-cans).在人阴道上皮细胞VK2/E6E7细胞C.albicans感染模型中,采用RT-qPCR检测各组细胞炎症因子IL-17A、IL-17F、IL-36α、IL-36β、IL-36γ的mRNA表达水平;ELISA检测各组细胞炎症因子蛋白表达水平.在人CD4+初始T淋巴细胞C.albicans感染模型中,采用Western blot检测各组JAK(1-3)及STAT(1-3)磷酸化水平;采用流式细胞术检测T细胞表型标志物CD45R0、CD69、CD103的表达.结果 在 C.albicans 感染的 VK2/E6E7 细胞中,促炎因子(IL-17A、IL-17F、IL-36α、IL-36β、IL-36γ)表达较空白组显著上调(P＜0.01),E2+C.albicans组的促炎因子表达较C.albicans组显著下调(P＜0.01).在人CD4+初始T细胞中,C.albicans组的JAK(1-2)及STAT(1-2)磷酸化程度较空白组显著增加(P＜0.05),E2+C.albicans 组的 JAK(1-2)及 STAT(1-2)磷酸化程度较 C.albicans 组显著降低(P＜0.05),而JAK3与STAT3磷酸化水平无显著变化(P＞0.05).此外,E2组较空白组显著下调CD45RO、CD69表达(P＜0.001),并上调CD103表达(P＜0.001).结论 E2可下调阴道上皮细胞VK2/E6E7 C.albi-cans 感染模型促炎因子IL-17A、IL-17F、IL-36α、IL-36β、IL-36γ的表达,且E2可不同程度抑制人CD4+初始T淋巴细胞C.albicans感染模型JAK(1-2)及STAT(1-2)磷酸化.E2通过调控JAK/STAT信号通路,重塑CD4+T细胞的活化与组织驻留表型,从而削弱阴道局部的抗真菌免疫清除能力,促进复发性外阴阴道念珠菌病的发生发展.
Objective To explore the effects of estradiol(E2)on the expression of epithelial cell inflammatory cytokines(IL-17/IL-36 family),as well as on JAK/STAT phosphorylation and phenotypic differentiation of T cells.Methods C.albicans infection models were established using VK2/E6E7 cells and human CD4+naïve T lymphocytes,respectively.Both models were divided into four groups:a control group,an E2 group(containing 10-8 mol/L E2),a C.albicans group(containing 1 × 106 cfu/mL C.albicans),and a C.albicans+E2 group(containing 10-8 mol/L E2 and 1 × 106 cfu/mL C.albicans).In the VK2/E6E7 cell model,the expression levels of mR-NA for inflammatory cytokines,including IL-17A,IL-17F,IL-36α,IL-36β,and IL-36γ,were detected by RT-qPCR,while protein levels were measured by ELISA.In the CD4+naïve T lym-phocyte model,the phosphorylation levels of JAK(1-3)and STAT(1-3)were detected by Western blot,and the expression levels of T cell phenotypic markers,such as CD45R0,CD69,and CD103,were analyzed by flow cytometry.Results In C.albicans-infected VK2/E6E7 cells,the expression levels of pro-inflammatory cytokines(IL-17A,IL-17F,IL-36α,IL-36β,and IL-36γ)were significantly upregulated compared to the control group(P＜0.01).In contrast,the E2+C.albicans group significantly downregulated expression of these cytokines compared to the C.albi-cans group(P＜0.01).In human CD4+naïve T cells,phosphorylation levels of JAK(1-2)and STAT(1-2)were significantly increased in the C.albicans group compared to the control group(P＜0.05),and were significantly decreased in the E2+C.albicans group compared to the C.al-bicans group(P＜0.05),while no significant changes were observed for JAK3 and STAT3(P＞0.05).Additionally,the E2 group showed significant downregulation of CD45RO and CD69 ex-pression(P＜0.001)and significant upregulation of CD103 expression(P＜0.001)compared to the control group.Conclusions E2 downregulates the expression levels of pro-inflammatory cyto-kines(IL-17A,IL-17F,IL-36 α,IL-36β,IL-36γ)in C.albicans-infected vaginal epithelial cells and inhibits C.albicans-induced phosphorylation of JAK(1-2),STAT(1-2)in human CD4+naïve T lymphocytes.By inhibiting the JAK/STAT signaling pathway,E2 reshapes the activation and tissue-residency phenotypes of CD4+T cells,thereby impairing local antifungal immune clear-ance and promoting the pathogenesis of recurrent vulvovaginal candidiasis.
李恺欣;魏娜;李思齐;钟莉;刘蔚;梁小爽;林映萍;陈嵘祎
南方医科大学皮肤病医院,广东 广州 510091南方医科大学皮肤病医院,广东 广州 510091南方医科大学皮肤病医院,广东 广州 510091南方医科大学皮肤病医院,广东 广州 510091南方医科大学皮肤病医院,广东 广州 510091南方医科大学皮肤病医院,广东 广州 510091东莞市第六人民医院,广东 东莞 523129南方医科大学皮肤病医院,广东 广州 510091
复发性外阴阴道念珠菌病白念珠菌雌二醇炎症因子JAK/STAT通路CD4+初始T淋巴细胞
recurrent vulvovaginal candidiasisCandida albicansestradiolinflammato-ry cytokinesJAK/STAT signaling pathwayCD4+naïve T lymphocytes
《皮肤性病诊疗学杂志》 2026 (4)
243-252,10
东莞市社会科技发展重点项目(20221800905452)南方医科大学皮肤病教改课题(ZP202401)
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