Macrophages Protect Endometriotic Cells Against Oxidative Damage Through a Cross-Talk Mechanism

Kenji Ogawa, Ogawa K, Liu T, Tingting Liu, Naoki Kawahara, Kawahara N, Hiroshi Kobayashi
Reproductive sciences (Thousand Oaks, Calif.) · 2022 · vol. 29(8) , pp. 2165–2178 · doi:10.1007/s43032-022-00890-6 · PMID:35199318 · W4213415670
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⚙ AI-generated summary by claude@2026-06+body, 2026-06-13 ⓘ

Macrophages protect endometriotic cells from oxidative damage via a cross-talk mechanism involving TGF-β1 and heme oxygenase-1.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 · read from full text ⓘ

The study investigated whether macrophages protect endometrial cells from oxidative injury and what mechanism mediates this protection. Differentiated THP-1 macrophage-like cells were co-cultured with cultured endometrial cells (dTHP-1), then exposed to hydrogen peroxide or methemoglobin-containing fluid; gene expression profiling (microarray, DEG screening/verification) and functional assays with inhibitors were used. Co-culture altered endometrial cell gene expression, with TGF-β1 identified as a key candidate, and TGF-β1 was shown to induce macrophage heme oxygenase-1 (HO-1); oxidative stress increased HO-1 further during co-culture, and this macrophage protection of endometrial cells required HO-1 because HO-1 inhibition abolished it. Relevance to endometriosis: the paper concludes that macrophage–endometrial cell cross-talk via TGF-β1/HO-1 may contribute to endometriosis progression and pathogenesis, and it directly centers on endometriotic cell protection from oxidative damage.

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Abstract

This aim of this study was to investigate whether macrophages protect endometriotic cells from oxidative injury and to elucidate the underlying mechanisms of any protection. Endometriotic cells cultured with or without differentiated macrophages (dTHP-1 cells) were treated with hydrogen peroxide (H2O2) or methemoglobin, a major component of hemoglobin species in endometriotic cyst fluid. Co-culture experiments, microarray analysis, screening and validation of differentially expressed genes (DEGs), cell proliferation and viability assays, and experiments using a specific inhibitor were conducted to investigate the functional cross-talk between endometriotic cells and macrophages. Microarray analysis revealed that endometriotic cells co-cultured with dTHP-1 differentially express several genes compared with monoculture. Quantitative enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis identified TGF-β1 as a promising candidate gene expressed in endometriotic cells co-cultured with dTHP-1 cells. TGF-β1 stimulated the expression of heme oxygenase-1 (HO-1) in dTHP-1 cells. HO-1 expression was increased in dTHP-1 cells co-cultured with endometriotic cells compared with the dTHP-1 monoculture. Both H2O2 and methemoglobin upregulated the expression of the HO-1 protein in the dTHP-1 monoculture; moreover, co-culture with endometriotic cells further enhanced HO-1 production. The co-culture with dTHP-1 protected endometriotic cells against oxidative injury. Blockade of HO-1 abolished the protective effects of macrophages. In an oxidative stress environment, TGF-β1 produced by endometriotic cells may protect against oxidative injury through the upregulation of macrophage-derived HO-1. The cross-talk between endometriotic cells and macrophages may contribute to the progression and pathogenesis of endometriosis.
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様式第５-１号（第７条関係） 論 文 内 容 の 要 旨 氏 名 小川 憲二 Macrophages Protect Endometriotic Cells Against Oxidative Damage Through a Cross-Talk Mechanism ( 和 訳 ) マクロファージはクロストーク機構により子宮内膜細胞を酸化ストレスから保護 する 論文内容の要旨 本研究の目的は、マクロファージが子宮内膜細胞を酸化傷害から保護するかどうかを調 べ、その保護メカニズムの根底を明らかにすることである。分化したマクロファージと培 養した子宮内膜細胞（dTHP-1 細胞）を、過酸化水素（H2O2）または子宮内膜症性嚢胞の 内容液中のヘモグロビン種の主要成分であるメトヘモグロビンで処理した。子宮内膜細 胞とマクロファージの機能的クロストークを調べるために、共培養実験、マイクロアレイ解 析、微量発現遺伝子（DEG）のスクリーニングと検証、細胞増殖と生存率のアッセイ、特異 的阻害剤を用いた実験を行った。マイクロアレイ解析の結果、dTHP-1 と共培養した子宮 内膜細胞は、単培養と比較していくつかの遺伝子の発現が異なることが判明した。定量 的酵素結合免疫吸着法（ELISA）およびウェスタンブロッティング解析により、TGF-β1 が dTHP-1 細胞と共培養した子宮内膜細胞で発現する有望な候補遺伝子として同定された。 TGF-β1 は、dTHP-1 細胞のヘムオキシゲナーゼ-1（HO-1）の発現を刺激した。子宮内膜 炎細胞と共培養したdTHP-1 細胞では、dTHP-1 単培養に比べHO-1 の発現が増加した。 H2O2 とメトヘモグロビンの両方が dTHP-1 単培養体の HO-1 タンパク質の発現を上昇さ せ、さらに子宮内膜細胞との共培養によりHO-1 の産生がさらに促進された。dTHP-1 との 共培養は、子宮内膜細胞を酸化ストレスから保護した。HO-1 を阻害すると、マクロファー ジの保護作用は消失した。酸化ストレス環境において、子宮内膜細胞の産生する TGF- β1 は、マクロファージ由来の HO-1 のアップレギュレーションを通じて、細胞障害から保 護する可能性がある。子宮内膜細胞とマクロファージのクロストークは、子宮内膜症の 進行と病態形成に寄与している可能性がある。

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endometriosis

MeSH descriptors

Endometriosis Endometriosis Transforming Growth Factor beta1 Transforming Growth Factor beta1 Female Heme Oxygenase-1 Heme Oxygenase-1 Humans Hydrogen Peroxide Hydrogen Peroxide Macrophages Macrophages Methemoglobin Methemoglobin Methemoglobin Oxidative Stress

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