17β-estradiol inhibits the production of RANTES in human keratinocytes
17β-estradiol inhibits the production of RANTES in human keratinocytes
复制标题
DOI：
10.1046/j.1523-1747.2003.12067.x
复制
发表时间：
2003-03-01
影响因子：
6.5
通讯作者：
Watanabe, S
中科院分区：
文献类型：
--
作者：
Kanda, N;Watanabe, S
RANTES是一种受激活后调节的正常T细胞表达和分泌的趋化因子，可吸引T辅助细胞和巨噬细胞。在银屑病皮损的角质形成细胞中RANTES的产生增加，这可能是导致炎症渗透的原因之一。众所周知，雌激素调节牛皮癣的自然病程。我们在体外观察了17β-雌二醇对人角质形成细胞产生RANTES的影响。17β-雌二醇抑制肿瘤坏死因子-α或白介素1β诱导的角质形成细胞RANTES的分泌、mRNA表达和启动子活性，这些作用可被雌激素受体拮抗剂ICI 182 780所拮抗。RANTES启动子上的两个核因子kappaB元件是肿瘤坏死因子-α或白介素1-β诱导转录所必需的，并参与17-β-雌二醇的抑制作用。17β-雌二醇抑制核因子kappaB转录活性，但不抑制核因子kappaB与DNA的结合，也不抑制核因子kappaBα抑制物在肿瘤坏死因子α或白介素1β刺激下的磷酸化或降解。17β-雌二醇对核因子kappaB转录活性和RANTES启动子活性的抑制可被辅活化子cAMP反应元件结合蛋白(CREB)或核因子kappaB p65的过度表达所挽救，但不能被类固醇受体辅活化子-1或核因子kappaB p50所挽救。CREB结合蛋白的过表达挽救了17β雌二醇诱导的转录抑制，GAL4-P65(286-551)嵌合蛋白含有GAL4 DNA结合区和P65的C端反式激活结构域(氨基酸286-551)。将雌激素受体α或雌激素受体β导入雌激素受体阴性的SKBR3细胞后，17β-雌二醇通过GAL4-p65(286-551)抑制转录。这些结果表明，17β-雌二醇结合的雌激素受体可能通过与p65竞争CREB结合蛋白的限量而抑制核因子kappaB依赖的RANTES基因转录。
A chemokine, regulated upon activation, normal T cell expressed and secreted (RANTES) attracts T helper-1 cells and macrophages. The production of RANTES is enhanced in keratinocytes of psoriatic skin lesions, which may contribute to the inflammatory infiltrate. It is known that estrogen regulates the natural course of psoriasis. We examined the in vitro effects of 17beta-estradiol on RANTES production by human keratinocytes. 17beta-estradiol inhibited tumor necrosis factor-alpha or interleukin-1beta-induced RANTES secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of 17beta-estradiol were counteracted by estrogen receptor antagonist ICI 182 780. Two nuclear factor kappaB elements on RANTES promoter were required for tumor necrosis factor-alpha or interleukin-1beta-induced transcription and involved in the inhibition by 17beta-estradiol. 17beta-estradiol inhibited nuclear factor kappaB transcriptional activity, whereas it did not inhibit DNA binding of nuclear factor kappaB or phosphorylation or degradation of the inhibitor of nuclear factor kappaB alpha in tumor necrosis factor-alpha or interleukin-1beta-stimulated keratinocytes. 17beta-estradiol-induced inhibition of nuclear factor kappaB transcriptional activity and RANTES promoter activity was rescued by overexpression of a coactivator cyclic AMP response element-binding protein (CREB) or nuclear factor kappaB p65 but not by steroid receptor coactivator-1 or nuclear factor kappaB p50. The overexpression of CREB-binding protein rescued 17beta-estradiol-induced inhibition of transcription mediated by a chimeric protein, GAL4-p65(286-551), which contained GAL4 DNA binding domain fused to C-terminal transactivating domain of p65 (amino acids 286-551). The transfection of estrogen receptor alpha or estrogen receptor beta into estrogen receptor-negative SKBR3 cells resulted in 17beta-estradiol-mediated inhibition of transcription via GAL4-p65(286-551). These results suggest that 17beta-estradiol-bound estrogen receptor may inhibit nuclear factor kappaB-dependent transcription of RANTES gene by competing with p65 for limiting amounts of CREB-binding protein.