The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway.
The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway.
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DOI：
10.1111/micc.12364
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
von der Weid PY
中科院分区：
文献类型：
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作者：
Chen Y;Rehal S;Roizes S;Zhu HL;Cole WC;von der Weid PY
肠系膜淋巴管泵送对于将淋巴细胞和免疫细胞从肠粘膜推进到肠系膜淋巴结很重要，在肠道炎症期间受到损害。本研究的目的是检验促炎细胞因子肿瘤坏死因子α（TNF-α）是炎症诱导的淋巴收缩功能障碍的重要贡献者的假设，并确定其作用模式。在有或没有TNF-α的情况下孵育24小时后，从安装在压力肌描记器上的离体大鼠肠系膜淋巴管获得收缩参数。给予各种抑制剂，并应用定量实时PCR、蛋白质印迹和免疫荧光共聚焦成像来表征TNF-α作用的机制。TNF-α处理后血管收缩频率显著降低，选择性抑制NF-B、iNOS、鸟苷酸环化酶和ATP敏感性K+通道可使收缩频率恢复。我们进一步证明，NF-κ B抑制也抑制了TNF-α处理的淋巴管中观察到的iNOS mRNA的显著增加，并且TNF-α处理有利于p65 NF-κB亚基的核转位。这些结果表明TNF-α通过激活NF-κB - iNOS信号通路降低肠系膜淋巴管收缩力。这种机制可能有助于改变淋巴泵在肠道炎症报告。
Mesenteric lymphatic vessels pumping, important to propel lymph and immune cells from the intestinal interstitium to the mesenteric lymph nodes, is compromised during intestinal inflammation. The objective of this study was to test the hypothesis that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α), is a significant contributor to the inflammation-induced lymphatic contractile dysfunction, and to determine its mode of action. Contractile parameters were obtained form isolated rat mesenteric lymphatic vessels mounted on a pressure myograph after 24-h incubation with or without TNF-α. Various inhibitors were administered and quantitative real-time PCR, western blotting and immunofluorescence confocal imaging were applied to characterize the mechanisms involved in TNF-α actions. Vessel contraction frequency was significantly decreased after TNF-α treatment and could be restored by selective inhibition of NF-кB, iNOS, guanylate cyclase and ATP-sensitive K+ channels. We further demonstrated that NF-кB inhibition also suppressed the significant increase in iNOS mRNA observed in TNF-α-treated lymphatic vessels and that TNF-α treatment favor the nuclear translocation of the p65 NF-κB subunit. These findings suggest that TNF-α decreases mesenteric lymphatic contractility by activating the NF-κB - iNOS signaling pathway. This mechanism could contribute to the alteration of lymphatic pumping reported in intestinal inflammation.