Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture
Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture
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DOI：
10.1097/01.shk.0000157301.87051.77
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发表时间：
2005-04-01
期刊：
影响因子：
3.1
通讯作者：
Stenson, WF
中科院分区：
文献类型：
--
作者：
Ebach, DR;Riehl, TE;Stenson, WF
肿瘤坏死因子（TNF）-α是脓毒症诱导的宿主损伤级联反应中的主要分子，与两种不同的受体结合：肿瘤坏死因子受体（TNFR）1和TNFR 2。我们使用盲肠结扎穿孔模型的多微生物脓毒症，以阐明这些受体在脓毒症发病机制中的作用。缺乏TNFR 1的小鼠存活时间延长，体温降低，而缺乏TNFR 2-/-的小鼠存活时间缩短，体温降低程度高于野生型小鼠。与野生型小鼠相比，TNFR 1-/-和TNFR 2-/-小鼠的白细胞介素（IL）10和总TNF-α（游离+受体结合）的血清浓度增加，但IL 6或IL 10浓度没有差异。此外，在缺乏TNFR 2的小鼠的血清和腹腔液中，游离TNF-α显著升高，支持该受体在调节TNF-α浓度中的作用。最后，回肠隐窝上皮细胞的凋亡增加，在缺乏TNFR 1的小鼠，但淋巴细胞凋亡没有差异。这些数据表明，在脓毒症中，TNFR 1介导大部分TNF-α诱导的病理，而TNFR 2介导保护作用。
Tumor necrosis factor (TNF)-alpha, a cardinal molecule in the cascade of sepsis-induced host injury, binds to two distinct receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2. We used the cecal ligation and puncture model of polymicrobial sepsis to elucidate the role of these receptors in sepsis pathogenesis. Mice lacking TNFR1 had prolonged survival with less hypothermia, whereas mice lacking TNFR2-/- had shortened survival and more profound hypothermia than wild-type mice. TNFR1-/- and TNFR2-/- mice had increased serum concentrations of interleukin (IL) 10 and total TNF-alpha (free plus receptor bound) compared with wild-type mice, but there were no differences in IL6 or IL10 concentrations. Furthermore, free TNF-alpha was markedly elevated in the serum and peritoneal fluid of mice lacking TNFR2, supporting a role for this receptor in regulating the concentration of TNF-alpha. Lastly, apoptosis of ileal crypt epithelial cells was increased in mice lacking TNFR1, but there were no differences in lymphocyte apoptosis. These data suggest that in sepsis, TNFR1 mediates much of the TNF-alpha-induced pathology, whereas TNFR2 mediates protective effects.