Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis
Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis
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DOI：
10.1096/fj.10.165050
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Yoshiko Iizuka;T. Okuno;Kazuko Saeki;H. Uozaki;Shinji Okada;T. Misaka;Tetsuya Sato;H. Toh;M. Fu
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文献类型：
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作者：
Yoshiko Iizuka;T. Okuno;Kazuko Saeki;H. Uozaki;Shinji Okada;T. Misaka;Tetsuya Sato;H. Toh;M. Fu
BLT 2是一种低亲和力白三烯B4（LTB 4）受体，可被12（S）-羟基十七碳-5Z，8 E，10 E-三烯酸（12-HHT）和LTB 4激活。尽管BLT 1具有明确的促炎作用，但BLT 2的体内功能仍然难以捉摸。为了阐明BLT受体在肠道炎症中的作用，我们评估了缺乏BLT 1或BLT 2的小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎的易感性。与野生型和BLT 1_/_小鼠相比，BLT 2-/_小鼠表现出对DSS的敏感性增加，体重减轻和炎症更严重。在DSS处理的BLT 2-/-小鼠的结肠中，炎性细胞因子（如干扰素（IFN）-γ、白细胞介素（IL）-1 β和IL-6）、趋化因子（如CXC趋化因子配体9（CXCL 9）和C-C基序趋化因子19（CCL 19））和金属蛋白酶的表达高度上调，并且活化巨噬细胞的蓄积增强。在DSS处理的BLT 2_/_小鼠的隐窝中，信号转导和转录激活因子3（STAT 3）的磷酸化也显著加速。通过跨上皮电阻（TER）和通过MDCK单层的FITC-葡聚糖渗漏测量，BLT 2转染的Madin达比犬肾II（MDCKII）细胞显示屏障功能增强。因此，BLT 2在结肠隐蔽细胞中表达，并且似乎可以防止DSS诱导的结肠炎，可能是通过增强结肠上皮细胞中的屏障功能。这些新的结果表明，BLT 2的直接抗炎作用与BLT 1的促炎作用不同。Iizuka，Y.，Okuno，T.，Saeki，K.，Uozaki，H.，Okada，S.，Misaka，T.，佐藤，T.，Toh，H.，Mr. Jakayama，M.，Takeda，N.，Kita，Y.，Shimizu，T.，中村，M.，Yokomizo，T.白三烯B4受体BLT 2在小鼠炎症性结肠炎中的保护作用。FASEB J.24，4678-4690（2010）。www.fasebj.org
BLT2 is a low‐affinity leukotriene B4 (LTB4) receptor that is activated by 12(S)‐hydroxyhep‐tadeca‐5Z,8E,10E‐trienoic acid (12‐HHT) and LTB4. Despite the well‐defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. To clarify the role of BLT receptors in intestinal inflammation, we assessed susceptibility to dextran sodium sulfate (DSS)‐induced colitis in mice lacking either BLT1 or BLT2. BLT2–/– mice exhibited increased sensitivity to DSS as compared to wild‐type and BLT1_/_ mice, with more severe body weight loss and inflammation. Expression of inflammatory cytokines such as interferon (IFN)‐γ, interleukin (IL)‐1β, and IL‐6, chemokines such as CXC chemokine ligand 9 (CXCL9) and C‐C motif chemokine 19 (CCL19), and metalloproteinases was highly up‐regulated in the colons of DSS‐treated BLT2–/– mice, and there was an enhanced accumulation of activated macrophages. Phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was also markedly accelerated in the crypts of DSS‐treated BLT2_/_ mice. Madin‐Darby canine kidney II (MDCKII) cells transfected with BLT2 exhibited enhanced barrier function as measured by transepithelial electrical resistance (TER) and FITC‐dextran leakage through MDCK monolayers. Thus, BLT2 is expressed in colon cryptic cells and appears to protect against DSS‐induced colitis, possibly by enhancing barrier function in epithelial cells of the colon. These novel results suggest a direct anti‐inflammatory role of BLT2 that is distinct from the proinflammatory roles of BLT1.—Iizuka, Y., Okuno, T., Saeki, K., Uozaki, H., Okada, S., Misaka, T., Sato, T., Toh, H., Fukayama, M., Takeda, N., Kita, Y., Shimizu, T., Nakamura, M., Yokomizo, T. Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis. FASEB J. 24, 4678–4690 (2010). www.fasebj.org