[논문]자궁내막 염증에 대한 지엽적 에스트로겐 및 프로게스테론 매개 수용체의 역할

민계식

doi:10.5352/jls.2023.33.1.102

자궁내막 염증에 대한 지엽적 에스트로겐 및 프로게스테론 매개 수용체의 역할
Roles of Local Estrogen and Progesterone Mediated Receptors in the Regulation of Endometrial Inflammation 원문보기

생명과학회지 = Journal of life science, v.33 no.1, 2023년, pp.102 - 113

민계식 (경상국립대학교 간호대학 간호학과)

초록
AI-Helper

본 총설에서는 지난 수년 동안 자궁내막 염증 관련 새롭게 밝혀진 에스트로겐과 프로게스테론 수용체의 기능 중 지엽적 에스트로겐의 합성, 특이적 에스트로겐 수용체의 조절, 프로게스테론 저항성 그리고 스테로이드 호르몬의 작용에 의한 자궁내막 조직세포의 염증반응, 분화 및 생존에 대한 세포 및 분자적 조절기전들을 고찰한다. 자궁내막 조직 기질세포의 비정상적인 후성유전체적 변화는 자궁내막증의 발병과 진행에 중요한 요인으로 작용한다. 특히, 에스트로겐 수용체 유전자들의 차별적 메틸화는 기질세포내 ERα로부터 ERβ로의 발현 우세도 전환을 유도하여, ERβ-매개 염증반응, 프로게스테론 저항성 및 레티노이드 합성장애 등의 비정상적인 에스트로겐 반응을 초래한다. 이 기질세포는 또한 PGE2 및 SF-1 매개에 의한 스테로이드 합성효소의 발현유도를 통하여 지엽적 에스트로겐의 생성을 촉진하며, 증가된 에스트라디올은 다시 ERβ에 피드백으로 작용하여 COX-2 촉진을 통한 염증반응의 악순환을 야기한다. 높은 ERβ의 발현은 중간엽 줄기세포의 염색질 구조변화릉 야기하여 프로게스테론 저항성을 획득하고, 이는 반복적 생리에 따른 지속적 노출로 자궁내막 조직의 염증을 형성하며, 이후에는 ERβ-매개 에스트로겐과 TNF-α 및 TGF-β1을 포함한 염증 유발 인자들이 작용하여 염증 조직세포의 부착, 혈관생성 및 생존과 기질세포의 분화조절장애를 유도한다. 따라서, 생리주기의 역동적인 호르몬 변화와 이에 따르는 자궁내막 조직의 핵수용체 신호전달 조절기전에 대한 구체적인 이해는 정상적인 생식기능을 유지하면서 자궁내막증과 같은 비정상적 염증질환을 치료하기 위한 새로운 안목을 제공할 수 있을 것으로 기대된다.

Abstract ▼ AI-Helper

This review discusses the cellular and molecular mechanisms by which the endometrial estrogen and progesterone receptors regulate local estrogen production, expression of the specific estrogen receptors, progesterone resistance, inflammatory responses and the differentiation and survival of endometriotic cells in endometrial inflammation. The epigenetic aberrations of endometrial stromal cells play an important role in the pathogenesis and progression of endometriosis. In particular, differential methylation of the estrogen receptor genes changes in the stromal cells the dominancy of estrogen receptor from ERα into ERβ, and results in the abnormal estrogen responses including inflammation, progesterone resistance and the disturbance of retinoid synthesis. These stromal cells also stimulate local estrogen production in response to PGE2 and the SF-1 mediated induction of steroidogenic enzyme expression, and the increased estradiol then feeds back into the ERβ to repeat the vicious inflammatory cycle through the activation of COX-2. In addition, high levels of ERβ expression may also change the chromatin structure of endometrial mesenchymal stem cells, and together with the repeated menstrual cycles can induce formation of the endometriotic tissue. The cascade of these serial events then leads to cell adhesion, angiogenesis and survival of the differentiation-disregulated stromal cells through the action of inflammatory factors such as ERβ-mediated estrogen, TNF-α and TGF-β1. Therefore, understanding of the dynamic hormonal changes during the menstrual cycle and the corresponding signal transduction mechanisms of the related nuclear receptors in endometrium would provide new insights for treating inflammatory diseases such as the endometriosis.

주제어

표/그림 (6)

그림 Fig. 1. Mechanisms in the regulation of gene expression for different isoforms of estrogen receptor and the ERβ- mediated pathological responses in endometrial inflammation. In endometriotic stromal cells, expression of ERβ gene is upregulated by hypomethylation in its promoter, whereas both estrogen-activated ERβ and DNA methyltransferase-mediated hypermethylation lead to the inhibition of ERα gene expression. High levels of ERβ stimulate COX-2 to increase production of PGE₂ which then triggers induction of genes and sev- eral different cellular signaling pathways involved in cell adhesion, anti-apoptosis, proliferation, angiogenesis and inflammation. Abbreviation: ER, estrogen receptor; DMT, DNA methyltransferase; E₂, 17β-estradiol; COX2, cyclooxygenase-2; PGE₂, prostaglandin E₂; SGK-1, serum and glucocorticoid-regulated kinase-1; PKA, protein kinase A; RERG, Ras-like and estrogen-regulated growth inhibitor; IL-1, interleukin-1; MAC, macrophage.
그림 Fig. 1. Mechanisms in the regulation of gene expression for different isoforms of estrogen receptor and the ERβ-mediated pathological responses in endometrial inflammation. In endometriotic stromal cells, expression of ERβ gene is upregulated by hypomethylation in its promoter, whereas both estrogen-activated ERβ and DNA methyltransferase-mediated hypermethylation lead to the inhibition of ERα gene expression. High levels of ERβ stimulate COX-2 to increase production of PGE2 which then triggers induction of genes and several different cellular signaling pathways involved in cell adhesion, anti-apoptosis, proliferation, angiogenesis and inflammation. Abbreviation: ER, estrogen receptor; DMT, DNA methyltransferase; E2, 17β-estradiol; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; SGK-1, serum and glucocorticoid-regulated kinase-1; PKA, protein kinase A; RERG, Ras-like and estrogen-regulated growth inhibitor; IL-1, interleukin-1; MAC, macrophage.
표 Table 1. Comparison in the production and activity of different inflammatory regulators between normal endometrium and endo- metriotic tissues
표 Table 1. Comparison in the production and activity of different inflammatory regulators between normal endometrium and endometriotic tissues
그림 Fig. 2. Cellular mechanisms of progesterone resistance in the endometriotic tissue. In endometriotic stromal cells, expression of progesterone receptors is downregulated by 1) ERβ-mediated blockade of ERα gene expression, 2) direct inhibition of PR gene expression acting as a transcriptional repressor, 3) hypermethylation in the PR gene promoter by pro-inflammatory cytokines and 4) micro RNAs. Decreased levels of PR fail to conduct in a paracrine fashion the progester- one-mediated PR inhibition of ERα gene expression in epithelial cells, resulting in cellular growth and proliferation. Lower PR levels also suppress production of retinoic acid in stromal cells capable of stimulating the expression of 17β- hydroxysteroid dehydrogenase type II enzyme by acting on the epithelial cells in a paracrine manner, resulting in increased levels of the biologically active 17β-estradiol. Abbreviation: ER, estrogen receptor; PR, progesterone receptor; TNF, tumor necrosis factor; RA, retinoic acid; E₂, 17β-estradiol; P, progesterone; miR, micro RNA; HSD17β2, 17β-hydroxysteroid dehydrogenase type II.
그림 Fig. 2. Cellular mechanisms of progesterone resistance in the endometriotic tissue. In endometriotic stromal cells, expression of progesterone receptors is downregulated by 1) ERβ-mediated blockade of ERα gene expression, 2) direct inhibition of PR gene expression acting as a transcriptional repressor, 3) hypermethylation in the PR gene promoter by pro-inflammatory cytokines and 4) micro RNAs. Decreased levels of PR fail to conduct in a paracrine fashion the progesterone-mediated PR inhibition of ERα gene expression in epithelial cells, resulting in cellular growth and proliferation. Lower PR levels also suppress production of retinoic acid in stromal cells capable of stimulating the expression of 17β-hydroxysteroid dehydrogenase type II enzyme by acting on the epithelial cells in a paracrine manner, resulting in increased levels of the biologically active 17β-estradiol. Abbreviation: ER, estrogen receptor; PR, progesterone receptor; TNF, tumor necrosis factor; RA, retinoic acid; E₂, 17β-estradiol; P, progesterone; miR, micro RNA; HSD17β2, 17β-hydroxysteroid dehydrogenase type II.

AI 본문요약
AI-Helper

성능/효과

결론적으로, 자궁내 및 자궁외 자궁내막조직에서 발생하는 자궁내막증은 비정상적인 후성유전체적 변화, 과잉의 에스트로겐 생성과 ERβ의 과발현으로 활성화되는 염증반응, 프로게스테론 저항성과 그에 따른 레티노이드 합성결핍으로 인한 지엽적인 활성형 에스트로겐의 가용성 증대 그리고 자궁내막 기질 중간엽 줄기세포의 발현조절 장애 등에 기인한 것으로 사료된다

후속연구

이러한 비정상적인 현상들은 결국 기질세포의 분화조절 장애, 세포부착, 혈관생성, 염증심화 및 세포사멸 억제에 따른 생존증가 등의 생물학적 결과를 초래한다. 그러므로, 생리주기의 역동적인 호르몬 변화와 이에 따르는 자궁내막 조직의 핵수용체 신호전달 조절기전에 대한 구체적인 이해는 정상적인 생식기능을 유지하면서 자궁내막증과 같은 비정상적 염증질환을 치료하기 위한 새로운 안목을 제공할 수 있을 것으로 기대된다.

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표제어: PCR

동의어: Packet Collision Rate

용어 설명 출처 목록 (6)

용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

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구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

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