Francoeur Caroline, Escaffit Fabrice, Vachon Pierre H, Beaulieu Jean-François
Canadian Institutes of Health Research Group in Functional Development and Physiopathology of the Digestive Tract, Département d'anatomie et de biologie cellulaire, Faculté de médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Am J Physiol Gastrointest Liver Physiol. 2004 Sep;287(3):G592-8. doi: 10.1152/ajpgi.00535.2003. Epub 2004 Apr 15.
Laminins are basement membrane molecules that mediate cell functions such as adhesion, proliferation, migration, and differentiation. In the normal small intestine, laminin-5 and -10 are mainly expressed at the base of villus cells. However, in Crohn's disease (CD), a major redistribution of these laminins to the crypt region of the inflamed ileal mucosa has been observed, suggesting a possible relationship between laminin expression and cytokine and/or growth factor production, which is also altered in CD. The aim of this study was to test the hypothesis that proinflammatory cytokines can modulate laminin expression by intestinal epithelial cells. The effect of TNF-alpha, IFN-gamma, IL-1beta, IL-6, and transforming growth factor (TGF)-beta was analyzed on the expression of laminins in the normal human intestinal epithelial crypt (HIEC) cell line. When treated with a single cytokine, HIEC cells secreted small amounts of laminin-5 and -10. Only TNF-alpha and TGF-beta induced a slight increase in the secretion of these laminins. However, in combination, TNF-alpha and IFN-gamma synergistically stimulated the secretion of both laminin-5 and -10 in HIEC cells. Transcript analyses suggested that the upregulation of the two laminins might depend on distinct mechanisms. Interestingly, the TNF-alpha and IFN-gamma combination was also found to significantly promote apoptosis. However, the effect of cytokines on the secretion of laminins was maintained even after completely blocking apoptosis by inhibiting caspase activities. These results demonstrate that laminin production is specifically modulated by the proinflammatory cytokines TNF-alpha and IFN-gamma in intestinal epithelial cells under an apoptosis-independent mechanism.
层粘连蛋白是基底膜分子，可介导细胞的黏附、增殖、迁移和分化等功能。在正常小肠中，层粘连蛋白-5和-10主要在绒毛细胞底部表达。然而，在克罗恩病（CD）中，已观察到这些层粘连蛋白在炎症性回肠黏膜隐窝区域出现主要的重新分布，这表明层粘连蛋白表达与细胞因子和/或生长因子产生之间可能存在关联，而在CD中这些细胞因子和生长因子也发生了改变。本研究的目的是检验促炎细胞因子可调节肠上皮细胞层粘连蛋白表达这一假说。分析了肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和转化生长因子（TGF）-β对正常人肠上皮隐窝（HIEC）细胞系中层粘连蛋白表达的影响。当用单一细胞因子处理时，HIEC细胞分泌少量的层粘连蛋白-5和-10。只有TNF-α和TGF-β能诱导这些层粘连蛋白分泌略有增加。然而，TNF-α和IFN-γ联合使用可协同刺激HIEC细胞中层粘连蛋白-5和-10的分泌。转录分析表明这两种层粘连蛋白的上调可能依赖于不同的机制。有趣的是，还发现TNF-α和IFN-γ联合使用能显著促进细胞凋亡。然而，即使通过抑制半胱天冬酶活性完全阻断细胞凋亡后，细胞因子对层粘连蛋白分泌的影响仍然存在。这些结果表明，在不依赖细胞凋亡的机制下，促炎细胞因子TNF-α和IFN-γ可特异性调节肠上皮细胞中层粘连蛋白的产生。
