Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis
Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis
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DOI：
10.4049/jimmunol.174.7.4193
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Nakao, A
中科院分区：
文献类型：
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作者：
Kanamaru, Y;Sumiyoshi, K;Nakao, A
肥大细胞在先天免疫和过敏反应中发挥着重要作用。然而，肥大细胞介导的先天免疫反应的调节机制仍然很大程度上未知。在这里，我们确定了 Smad3（TGF-β 的主要信号转导器）是否调节肥大细胞针对革兰氏阴性细菌的先天免疫反应。从 Smad3 缺失突变小鼠中获得的骨髓源性肥大细胞 (BMMC) 在受到革兰氏阴性菌相关产物 LPS 刺激后，显示出产生促炎细胞因子的能力增强。在盲肠结扎和穿刺诱导的急性脓毒性腹膜炎模型中，用Smad3缺失BMMC重建的肥大细胞缺陷W/W-v小鼠的存活率显着高于用野生型BMMC重建的W/W-v小鼠，这与腹膜腔中促炎细胞因子的较高产生有关。这些体外和体内结果表明，肥大细胞中的 Smad3 可以抑制肥大细胞介导的针对革兰氏阴性细菌的先天免疫反应。因此，抑制肥大细胞中的 Smad3 表达可能通过增强肥大细胞的先天免疫反应来治疗粒阴性细菌感染，例如急性脓毒性腹膜炎。
Mast cells play an important role in innate immunity as well as in allergic reaction. However, regulatory mechanisms underlying mast cell-mediated innate immune responses remain largely unknown. Here we determined whether Smad3, a major signal transducer of TGF-beta, regulates innate immune response by mast cells against Gram-negative bacteria. Bone marrow-derived mast cells (BMMC) obtained from Smad3 null mutant mice showed augmented capacity to produce proinflammatory cytokines upon stimulation with a Gram-negative bacteria-associated product, LPS. In acute septic peritonitis model induced by cecal ligation and puncture, mast cell-deficient W/W-v mice reconstituted with Smad3 null BMMC had significantly higher survival rate than W/W-v mice reconstituted with wild-type BMMC, which was associated with higher production of proinflammatory cytokines in the peritoneal cavity. These in vitro and in vivo results suggest that Smad3 in mast cells functions as inhibitory for mast cell-mediated innate immune response against Gram-negative bacteria. Suppression of Smad3 expression in mast cells may thus have therapeutic potential for Grain-negative bacterial infection such as acute septic peritonitis by augmenting innate immune responses of mast cells.