LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms
LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms
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DOI：
10.1053/j.gastro.2007.02.052
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发表时间：
2007-06-01
期刊：
影响因子：
29.4
通讯作者：
Turner, Jerrold R.
中科院分区：
文献类型：
--
作者：
Schwarz, Brad T.;Wang, Fengjun;Turner, Jerrold R.
背景与目的：LIGH(淋巴毒素样诱导蛋白，与糖蛋白D竞争疱疹病毒进入T细胞)是肿瘤坏死因子核心家族成员，调节T细胞活化，引起实验性炎症性肠病。更多数据表明，LIGH可能参与了人类炎症性肠病的发病机制。这项研究的目的是确定光是否能够直接向肠道上皮细胞传递信号，并确定这种信号传递的机制和后果。方法：观察光照和干扰素-γ对小鼠肠道上皮细胞屏障功能、细胞骨架调节和紧密连接结构的影响。结果：光通过肌球蛋白II调节轻链(MLC)的磷酸化导致培养上皮细胞屏障丧失，MLC激酶(MLCK)抑制可逆转屏障丧失和MLC磷酸化。这些效应需要诱导淋巴毒素β受体(LtoR)表达的干扰素-γ预先处理，而LT/βR基因敲除小鼠既没有屏障功能障碍，也没有肠上皮MLC磷酸化。在培养的单层细胞中，紧密连接蛋白occludin的内吞作用与屏障的丧失有关。内化闭塞蛋白与小窝蛋白-1共定位。光诱导的闭塞蛋白内吞作用和屏障丧失均可通过抑制空泡内吞作用来防止。结论：T细胞来源的LIGH可激活肠上皮细胞LTβR，从而破坏屏障功能。这需要MLCK的激活和空泡内吞作用。这些数据表明了LIGH在疾病发病机制中的新作用，并表明抑制MLCK依赖的空泡内吞作用可能是恢复炎症性肠病屏障功能的一种途径。
Background & Aims: LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a tumor necrosis factor core family member that regulates T-cell activation and causes experimental inflammatory bowel disease. Additional data suggest that LIGHT may be involved in the pathogenesis of human inflammatory bowel disease. The aim of this study was to determine if LIGHT is capable of signaling directly to intestinal epithelia and to define the mechanisms and consequences of such signaling. Methods: The effects of LIGHT and interferon-gamma on barrier function, cytoskeletal regulation, and tight junction structure were assessed in mice and intestinal epithelial monolayers. Results: LIGHT induced barrier loss in cultured epithelia via myosin II regulatory light chain (MLC) phosphorylation; both barrier loss and MLC phosphorylation were reversed by MLC kinase (MLCK) inhibition. Pretreatment with interferon-gamma, which induced lymphotoxin beta receptor (LTOR) expression, was required for these effects, and neither barrier dysfunction nor intestinal epithelial MLC phosphorylation occurred in LT/beta R knockout mice. In cultured monolayers, endocytosis of the tight junction protein occludin correlated with barrier loss. Internalized occludin colocalized with caveolin-1. LIGHT-induced occludin endocytosis and barrier loss were both prevented by inhibition of caveolar endocytosis. Conclusions: T cell-derived LIGHT activates intestinal epithelial LT beta R to disrupt barrier function. This requires MLCK activation and caveolar endocytosis. These data suggest a novel role for LIGHT in disease pathogenesis and suggest that inhibition of MLCK-dependent caveolar endocytosis may represent an approach to restoring barrier function in inflammatory bowel disease.