Markossian Sarine, Kreydiyyeh Sawsan Ibrahim
Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon.
Cytokine. 2005 Jun 21;30(6):319-27. doi: 10.1016/j.cyto.2004.11.009.
TNF-alpha is believed to play a pivotal role in the pathogenesis of inflammatory bowel diseases which have diarrhea as one of their symptoms. This work studies the effect of the cytokine on electrolyte and water movements in the rat distal colon using an intestinal perfusion technique and attempts to determine its underlying mechanism of action. TNF-alpha inhibited net water and chloride absorption, down-regulated in both surface and crypt colonocytes the Na+-K+-2Cl- cotransporter, and reduced the protein expression and activity of the Na+-K+ ATPase. Indomethacin up-regulated the pump and the cotransporter in surface cells but not in crypt cells, and in its presence, TNF-alpha could not exert its effect, suggesting an involvement of PGE2 in the cytokine action. The effect of TNF-alpha on the pump and symporter was studied also in cultured Caco-2 cells in isolation of the effect of other cells and tissues, to test whether the cytokine acts directly on intestinal cells. In these cells, TNF-alpha and PGE2 had a similar effect on the pump expression and activity as that observed in crypt cells but were without any effect on the Na+-K+-2Cl- cotransporter. It was concluded that the effect of the cytokine on colonocytes is mediated via PGE2. By inhibiting the Na+-K+ ATPase, it reduces the Na+ gradient needed for NaCl absorption, and by down-regulating the expression of the Na+-K+-2Cl- symporter, it reduces basolateral Cl- entry and luminal Cl- secretion. The inhibitory effect on absorption is more significant than the inhibitory effect on secretion resulting in a decrease in net electrolyte uptake and consequently in more water retention in the lumen.
肿瘤坏死因子-α（TNF-α）被认为在以腹泻为症状之一的炎症性肠病发病机制中起关键作用。本研究利用肠道灌注技术，研究了该细胞因子对大鼠远端结肠电解质和水转运的影响，并试图确定其潜在作用机制。TNF-α抑制水和氯离子的净吸收，下调结肠表面和隐窝细胞中的钠-钾-2氯协同转运体，并降低钠-钾ATP酶的蛋白表达和活性。吲哚美辛上调表面细胞而非隐窝细胞中的该泵和协同转运体，且在其存在的情况下，TNF-α无法发挥其作用，提示前列腺素E2（PGE2）参与了细胞因子的作用。还在分离了其他细胞和组织影响的情况下，在培养的Caco-2细胞中研究了TNF-α对该泵和同向转运体的影响，以测试该细胞因子是否直接作用于肠道细胞。在这些细胞中，TNF-α和PGE2对该泵表达和活性的影响与在隐窝细胞中观察到的相似，但对钠-钾-2氯协同转运体没有任何影响。得出的结论是，细胞因子对结肠细胞的作用是通过PGE2介导的。通过抑制钠-钾ATP酶，它降低了氯化钠吸收所需的钠梯度，通过下调钠-钾-2氯同向转运体的表达，它减少了基底侧氯离子的进入和管腔氯离子的分泌。对吸收的抑制作用比对分泌抑制作用更显著，导致净电解质摄取减少，从而使更多的水分滞留在管腔中。
