Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain.
Microvasc Res. 2011 May;81(3):261-8. doi: 10.1016/j.mvr.2011.01.006. Epub 2011 Jan 26.
Prostaglandin (PG) E(2) plays a key role in immune response, tumor progression and metastasis. We previously showed that macrovessel-derived endothelial cells do not produce PGE(2) enzymatically because they do not express the inducible microsomal PGE-synthase-1 (mPGES-1). Nevertheless, differences between macro- and micro-vessel-derived endothelial cells regarding arachidonic acid (AAc) metabolism profile have been reported. The present work was conducted to evaluate the expression of PGE(2)-pathway-related enzymes in human microvascular endothelial cells (HMVEC) in culture and to test the hypothesis that the tumor cell-HMVEC cross talk could increase mPGES-1 expression in HMVEC. We treated HMVEC in culture with human recombinant IL-1β. IL-1β induced PGE(2) release and COX-2 and mPGES-1 expression in terms of mRNA and protein, determined by real-time PCR and immunoblotting, respectively. HMVEC constitutively expressed mPGES-2 and cytosolic PGES (cPGES) and the IL-1β treatment did not modify their expression. PGE(2) synthesized by HMVEC from exogenous AAc was linked to mPGES-1 expression. Immunohistochemistry analysis confirmed mPGES-1 expression in microvessels in vivo. COX-2 and mPGES-1 were also induced in HMVEC by the conditioned medium from two squamous head and neck carcinoma cell lines. Conditioned medium from tumor cell cultures contained several cytokines including the IL-1β and IL-1α. Tumor cell-induced COX-2 and mPGES-1 in HMVEC was strongly inhibited by the IL-1-receptor antagonist, indicating the important implication of IL-1 in this effect. HMVEC could therefore contribute directly to PGE(2) formed in the tumor. Our findings support the concept that mPGES-1 could be a target for therapeutic intervention in patients with cancer.
前列腺素 (PG) E(2) 在免疫反应、肿瘤进展和转移中发挥关键作用。我们之前表明，大血管衍生的内皮细胞不会通过酶促产生 PGE(2)，因为它们不表达诱导型微粒体 PGE 合酶-1 (mPGES-1)。然而，已经报道了大血管和微血管衍生的内皮细胞之间在花生四烯酸 (AAc) 代谢谱方面的差异。本研究旨在评估人微血管内皮细胞 (HMVEC) 中 PGE(2) 途径相关酶的表达，并验证肿瘤细胞-HMVEC 串扰可增加 HMVEC 中 mPGES-1 表达的假设。我们用重组人白细胞介素 1β（IL-1β）处理培养中的 HMVEC。IL-1β 通过实时 PCR 和免疫印迹分别诱导 PGE(2) 释放以及 COX-2 和 mPGES-1 的 mRNA 和蛋白表达。HMVEC 持续表达 mPGES-2 和胞质 PGES (cPGES)，而 IL-1β 处理并未改变它们的表达。HMVEC 从外源性 AAc 合成的 PGE(2) 与 mPGES-1 表达相关。免疫组织化学分析证实了体内微血管中 mPGES-1 的表达。两种头颈部鳞状细胞癌细胞系的条件培养基也诱导了 HMVEC 中 COX-2 和 mPGES-1 的表达。肿瘤细胞培养物的条件培养基含有多种细胞因子，包括白细胞介素 1β 和白细胞介素 1α。IL-1 受体拮抗剂强烈抑制肿瘤细胞诱导的 HMVEC 中 COX-2 和 mPGES-1，表明 IL-1 在这种作用中具有重要意义。因此，HMVEC 可能直接有助于肿瘤中形成的 PGE(2)。我们的发现支持了 mPGES-1 可能成为癌症患者治疗干预的靶点的概念。
