Tumor necrosis factor-alpha induces Cl- and K+ secretion in human distal colon driven by prostaglandin E2.
Tumor necrosis factor-alpha induces Cl- and K+ secretion in human distal colon driven by prostaglandin E2.
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肿瘤坏死因子-α 在前列腺素 E2 的驱动下诱导人类远端结肠中 Cl 和 K 的分泌。
DOI：
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发表时间：
1996
影响因子：
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通讯作者：
J. Schulzke
中科院分区：
文献类型：
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作者：
H. Schmitz;Michael Fromm;H. Bode;P. Scholz;E. Riecken;J. Schulzke
例如，在炎症性肠病（IBD）和人类免疫缺陷病毒（HIV）感染中发现肿瘤坏死因子-α（TNF-α）水平升高。为了研究 TNF-α 对这些疾病中腹泻发病机制的可能贡献，在体外尤斯室中研究了人远端结肠的离子转运。浆膜中添加 TNF-α 会以剂量依赖性方式增加部分剥离组织的短路电流 (Isc)。在 200 ng/ml TNF-α 下 60 +/- 9 分钟后，Isc 最大增加为 1.8 +/- 0.2 mumol.h-1.cm-2。双向示踪剂通量测量表明，TNF-α 诱导 36 Cl 浆膜至粘膜通量增加、 36 Cl- 粘膜至浆膜通量减少，以及分泌性 86Rb 净通量增加表明 K+ 分泌略有增加。在高度分化的结肠上皮细胞系 HT-29/B6 中，TNF-α 对 Isc 没有影响，表明介导步骤位于上皮下。这一假设得到了对完全剥离的人体组织的测量的支持，因为通过完全剥离去除上皮下层使 TNF-α 效应降低了 40%。河豚毒素(10(-6)M)实验表明TNF-α效应不是由肠神经系统介导的。特异性5-脂氧合酶阻滞剂ICI-230487 (5 x 10(-8)M)对TNF-α作用也没有影响。相反，吲哚美辛 (10(-6)M) 抑制环氧合酶可抑制 TNF-α 的作用。对浆膜浴液中前列腺素 E2 (PGE2) 的放射免疫分析显示，添加 TNF-α 后 PGE2 的产生/释放增加，这与 Isc 反应平行。我们得出结论，TNF-α 改变了人结肠中 Cl- 和 K+ 的转运向分泌的方向。这种作用是由 TNF-α 产生的 PGE2 介导的。因此，TNF-α 可能是肠道炎症（例如 IBD 和 HIV 感染）期间腹泻的介质。
Increased levels of tumor necrosis factor-alpha (TNF-alpha) have been found in, for example, inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection. To investigate a possible contribution of TNF-alpha to the pathogenesis of diarrhea in these diseases, ion transport of human distal colon was studied in the Ussing chamber in vitro. Serosal addition of TNF-alpha increased short-circuit current (Isc) of partially stripped tissues in a dose-dependent manner. Maximum Isc increase of 1.8 +/- 0.2 mumol.h-1.cm-2 was reached after 60 +/- 9 min at 200 ng/ml TNF-alpha. Bidirectional tracer flux measurements revealed that TNF-alpha induced an increase in 36 Cl serosal-to-mucosal flux, a decrease in 36Cl- mucosal-to-serosal flux, and a slight increase in K+ secretion indicated by an increased secretory 86Rb net flux. In the highly differentiated colonic epithelial cell line HT-29/B6, TNF-alpha had no effect on Isc, suggesting a mediation step located in the subepithelium. This supposition was supported by measurements on totally stripped human tissues, since removal of subepithelial layers by total stripping reduced the TNF-alpha effect by 40%. Experiments with tetrodotoxin (10(-6)M) indicated that the TNF-alpha effect was not mediated by the enteric nervous system. The specific 5-lipoxygenase blocker ICI-230487 (5 x 10(-8)M) also had no effect on TNF-alpha action. In contrast, inhibition of cyclooxygenase by indomethacin (10(-6)M inhibited the effect of TNF-alpha. Radioimmunoassay of prostaglandin E2 (PGE2) in the serosal bathing solution revealed an increase in PGE2 production/release after addition of TNF-alpha, which paralleled the Isc response. We conclude that TNF-alpha changed Cl- and K+ transport toward secretion in human colon. This effect was mediated by PGE2 produced by subepithelial cells. Thus TNF-alpha could be a mediator of diarrhea during intestinal inflammation, e.g., in IBD and HIV infection.