Estradiol upregulates calcineurin expression via overexpression of estrogen receptor alpha gene in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease primarily affecting women (9:1 compared with men). To investigate the influence of female sex hormone estrogen on the development of female-biased lupus, we compared the expression of estrogen receptor alpha (ERα) gene and protein levels as well as expression of T-cell activation gene calcineurin in response to estrogen in peripheral blood lymphocytes (PBLs) from SLE patients and normal controls. PBLs were isolated from 20 female SLE patients and 6 normal female controls. The amount of ERα protein in PBL was measured by flow cytometry. The expression of ERα and calcineurin messenger RNA was measured by semi-quantitative reverse transcription-polymerase chain reaction. Calcineurin phosphatase activity was measured by calcineurin assay kit. The expression of ERα messenger RNA and ERα protein was significantly increased (p = 0.001 and p = 0.023, respectively) in PBL from SLE patients compared with that from normal controls. In addition, the basal calcineurin in PBL from SLE patients was significantly higher (p = 0.000) than that from normal controls, and estrogen-induced expression of calcineurin was increased (p = 0.007) in PBL from SLE patients compared with that from normal controls, a 3.15-fold increase. This increase was inhibited by the ERα antagonism ICI 182,780. The effects of ER antagonism were also found in calcineurin activity. These data suggest that overexpression of ERα gene and enhanced activation of calcineurin in response to estrogen in PBL may contribute to the pathogenesis of female dominant in SLE.

摘要全身性紅斑狼瘡是一種自體免疫疾病，主要侵犯女性為主 (男女比為 1:9)。為探討女性雌激素如何影响紅斑狼瘡偏向女性發生而研究狼瘡病人與正常人週邊血液淋巴球之雌激素受體α 基因與蛋白的表現。我們收集了20 位女性之紅斑狼瘡病人與6位正常女性志願者為研究對象。雌激素受體α蛋白的表現是以流式細胞測定儀定量之。雌激素受體α 和蛋白質磷酸酶 3CA 信息核醣核酸之測定是以半定量之逆轉錄鏈聚合反應測定之。蛋白質磷酸酶 3CA 之活度是以蛋白質磷酸酶分析用成套工具測定之。結果發現紅斑狼瘡周邊血淋巴球雌激素受體α之信息核醣核酸及蛋白的表現比正常人有意義增加，其 p 值分別為 0.001和 0.023。此外基礎之蛋白質磷酸酶 3CA 表現在紅斑狼瘡淋巴球比正常人有意義的增加，p 值=0.000。雌激素誘發之蛋白質磷酸酶 3CA 表現在紅斑狼瘡淋巴球比正常人有意義的增加 (p=0.007), 其增加為 3.15 倍, 此增加可被雌激素受體拮抗者ICI 182,780 抑制。雌激素受體拮抗現象亦發生於蛋白質磷酸酶 3CA 之磷酸酶活度。由以上結果顯示雌激素受體 α 基因的過度表現以及淋巴球因雌激素之刺激所導致蛋白質磷酸酶 3CA 之高度活化結果對狼瘡病人之偏向女性之致病機轉有所貢獻。