Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells.
Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells.
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DOI：
10.1210/jc.2010-2489
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发表时间：
2011-05
期刊：
影响因子：
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通讯作者：
I. Tamura;T. Taketani;L. Lee;Fumie Kizuka;K. Taniguchi;R. Maekawa;H. Asada;H. Tamura;N. Sugino
中科院分区：
文献类型：
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作者：
I. Tamura;T. Taketani;L. Lee;Fumie Kizuka;K. Taniguchi;R. Maekawa;H. Asada;H. Tamura;N. Sugino
孕酮对人子宫内膜基质细胞（ESC）中tnf α诱导的环氧化酶-2 （COX-2）和锰超氧化物歧化酶（Mn-SOD）基因表达的调节作用不同。目的探讨TNFα和黄体酮对ESC组织中COX-2和Mn-SOD表达的影响机制。方法ESC与TNFα、黄体酮孵育。实时RT-PCR检测COX-2和Mn-SOD mRNA的表达。核因子(NF)-κB结合启动子区或NF-κB反应元件的组蛋白乙酰化状态通过染色质免疫沉淀法分析。结果TNFα升高COX-2和Mn-SOD mRNA水平。黄体酮（10(-6)M）抑制tnf α诱导的COX-2 mRNA表达，而tnf α诱导的Mn-SOD表达不受黄体酮的抑制。通过小干扰RNA敲低孕激素受体，消除了孕激素的抑制作用。染色质免疫沉淀实验显示，TNFα增加了COX-2启动子和Mn-SOD增强子上NF-κB的结合，黄体酮仅抑制NF-κB在COX-2启动子上的结合。Mn-SOD增强子的NF-κB应答元件的组蛋白乙酰化水平低于COX-2启动子。然而，当组蛋白去乙酰化酶抑制剂诱导组蛋白乙酰化时，黄体酮抑制tnf α诱导的NF-κB与Mn-SOD增强子的结合。结论TNFα通过活化NF-κB增加COX-2和Mn-SOD的表达。黄体酮通过抑制NF-κB与其应答元件的结合来抑制COX-2的表达，但不抑制tnf α-诱导的Mn-SOD的表达。黄体酮的基因特异性作用可能与COX-2启动子和Mn-SOD增强子中NF-κB应答元件的染色质结构不同有关。
CONTEXT Progesterone differently regulates TNFα-induced gene expression of cyclooxygenase-2 (COX-2) and manganese superoxide dismutase (Mn-SOD) in human endometrial stromal cells (ESC). OBJECTIVE The present study investigated the mechanisms by which TNFα and progesterone affect the expressions of COX-2 and Mn-SOD in ESC. METHODS ESC were incubated with TNFα and progesterone. COX-2 and Mn-SOD mRNA expression was determined by real-time RT-PCR. Nuclear factor (NF)-κB binding to the promoter region or histone acetylation status of the NF-κB response element was analyzed by a chromatin immunoprecipitation assay. RESULTS TNFα increased COX-2 and Mn-SOD mRNA levels. Progesterone (10(-6) M) suppressed TNFα-induced COX-2 mRNA expression, whereas TNFα-induced Mn-SOD expression was not inhibited by progesterone. The inhibitory effect of progesterone was abolished by knockdown of progesterone receptors by small interfering RNA. Chromatin immunoprecipitation assay revealed that TNFα increased NF-κB binding at both the COX-2 promoter and the Mn-SOD enhancer and that progesterone inhibited only the NF-κB binding at the COX-2 promoter. The histone acetylation level of the NF-κB response element of the Mn-SOD enhancer was lower than that of the COX-2 promoter. However, when histone acetylation was induced by histone deacetylase inhibitors, progesterone inhibited the TNFα-induced NF-κB binding to the Mn-SOD enhancer. CONCLUSIONS TNFα increased COX-2 and Mn-SOD expression via NF-κB activation. Progesterone inhibited COX-2 expression by inhibiting the binding of NF-κB to its response element but did not inhibit TNFα-induced Mn-SOD expression. The gene-specific action of progesterone may be due to the difference in chromatin structure at the NF-κB response elements in the COX-2 promoter and Mn-SOD enhancer.