Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 antagonize TNF-α-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-α-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo
Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 antagonize TNF-α-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-α-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo
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DOI：
10.4049/jimmunol.167.5.2772
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发表时间：
2001-09-01
影响因子：
4.4
通讯作者：
MacMathuna, P
中科院分区：
文献类型：
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作者：
Goh, J;Baird, AW;MacMathuna, P
脂氧素(LXs)是脂氧合酶衍生的二十烷基类化合物，可能是胃肠道和其他器官炎症的内源性刹车信号。阿司匹林在细胞因子启动的环境中，在细胞-细胞相互作用过程中触发15-异构体的产生，而阿司匹林触发的15-epi-5(S)，6(R)，15(S)-trihydroxy-7，9，13-trans-11-cis-eicosatetraenoic酸(15-EPI-LXA(4))可能有助于这种原型非类固醇抗炎药物在体内的生物活性。我们研究了LXA(4)、15-(R/S)-甲基-11，12-脱氢-LXA(4)甲酯(15-(R/S)-甲基-LXA(4))及其稳定类似物对肿瘤坏死因子-α刺激的中性粒细胞-肠细胞相互作用和肿瘤坏死因子-α刺激的趋化因子释放、粘膜结构改变和细胞因子激活的肠上皮细胞凋亡的影响。LXA(4)、15-(R/S)-EPI-LXA(4)和16-phenoxy-11，12-dehydro-17，18，19，20-tetranor-LXA(4)甲酯(16-苯氧基-LXA(4))在纳摩尔浓度下可抑制肿瘤坏死因子-α刺激的中性粒细胞与上皮单分子层的黏附。在体外人结肠粘膜平行实验中，LXA(4)有效地减弱了肿瘤坏死因子-α刺激的C-X-C趋化因子IL-8、C-C趋化因子单核细胞趋化蛋白-1(MCP-1)和RANTES的释放。正常人结肠粘膜条状细胞暴露于肿瘤坏死因子-α可通过caspase-3非依赖性机制诱导粘膜结构破坏和促进结肠细胞凋亡。预先给予15-(RIS)-甲基-LXA(4)可减轻肿瘤坏死因子-α诱导的结肠细胞凋亡，保护粘膜免受肿瘤坏死因子-α诱导的粘膜损伤。总之，我们的数据表明，脂氧素和阿司匹林触发的15-epi-LXA(4)在体外可以有效地拮抗肿瘤坏死因子α介导的中性粒细胞与肠细胞的相互作用，减少肿瘤坏死因子α触发的趋化因子释放和结肠细胞凋亡，并对肿瘤坏死因子α诱导的体外人结肠条形态破坏具有保护作用。我们的观察进一步扩大了这些脂氧合酶衍生二十烷类化合物的抗炎作用，并为炎症性肠病的治疗提供了新的治疗方法。
Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA(4), 15-(R/S)-methyl-11,12-dehydro-LXA(4) methyl ester (15-(R/S)-methyl-LXA(4)), and stable analogs of LXA(4) on TNF-alpha -stimulated neutrophil-enterocyte interaction in vitro and TNF-alpha -stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA(4), 15-(R/S)-epi-LXA(4), and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) inhibited TNF-alpha -stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA(4)potently attenuated TNF-alpha -stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-alpha induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(RIS)-methyl-LXA(4) attenuated TNF-alpha -stimulated colonocyte apoptosis and protected the mucosa against TNF-alpha -induced mucosal damage. In aggregate, our data demonstrate that lipoxins; and aspirin-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha -mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-alpha -triggered chemokine release and colonocyte apoptosis, and are protective against TNF-alpha -induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.