Lajczak Natalia K, Saint-Criq Vinciane, O'Dwyer Aoife M, Perino Alessia, Adorini Luciano, Schoonjans Kristina, Keely Stephen J
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
FASEB J. 2017 Sep;31(9):3848-3857. doi: 10.1096/fj.201601365R. Epub 2017 May 9.
Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release. Effects of DCA were mimicked by the Takeda GPCR 5 agonist, INT-777 (50 μM), but not by the farnesoid X receptor agonist, GW4064 (10 μM). INT-777 also stimulated colonic HβD1 and HβD2 release from wild-type, but not Takeda GPCR 5, mice. DCA stimulated phosphorylation of the p65 subunit of NF-κB, an effect that was attenuated by ursodeoxycholic acid, whereas an NF-κB inhibitor, BMS-345541 (25 μM), inhibited DCA-induced HβD2, but not HβD1, release. We conclude that bile acids can differentially regulate colonic epithelial HβD expression and secretion and discuss the implications of our findings for intestinal health and disease.-Lajczak, N. K., Saint-Criq, V., O'Dwyer, A. M., Perino, A., Adorini, L., Schoonjans, K., Keely, S. J. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.
已知胆汁酸和上皮来源的人β-防御素（HβDs）是调节结肠黏膜屏障功能和炎症的重要因素。我们推测胆汁酸可调节结肠HβD的表达，并旨在通过研究脱氧胆酸（DCA）和熊去氧胆酸对结肠上皮细胞和黏膜组织中HβD1和HβD2表达及释放的影响来验证这一推测。DCA（10 - 150μM）刺激上皮细胞单层和人结肠黏膜组织释放HβD1和HβD2。相比之下，熊去氧胆酸（50 - 200μM）抑制基础状态和DCA诱导的防御素释放。武田GPCR 5激动剂INT - 777（50μM）可模拟DCA的作用，但法尼酯X受体激动剂GW4064（10μM）则不能。INT - 777还刺激野生型小鼠而非武田GPCR 5基因敲除小鼠的结肠HβD1和HβD2释放。DCA刺激NF - κB的p65亚基磷酸化，这一效应被熊去氧胆酸减弱，而NF - κB抑制剂BMS - 345541（25μM）抑制DCA诱导的HβD2释放，但不抑制HβD1释放。我们得出结论，胆汁酸可差异调节结肠上皮HβD的表达和分泌，并讨论了我们的发现对肠道健康和疾病的意义。-拉伊扎克，N.K.，圣克里克，V.，奥德怀尔，A.M.，佩里诺，A.，阿多里尼，L.，舒恩扬斯，K.，基利，S.J.脱氧胆酸和熊去氧胆酸差异调节结肠上皮细胞分泌人β-防御素-1和-2 。
