Vogel Megan E, Zucker Stephen D
Division of Digestive Diseases, University of Cincinnati, Cincinnati, 45267-0595, United States.
Inflamm Cell Signal. 2016;3(1). doi: 10.14800/ics.1178. Epub 2016 Feb 15.
There is a growing body of evidence that bilirubin, which is generated during the physiological breakdown of heme, exerts potent anti-inflammatory effects. Previous work by our group suggests that bilirubin is able to suppress inflammatory responses by preventing the migration of leukocytes into target tissues through disruption of vascular cell adhesion molecule-1 (VCAM-1)-dependent cell signaling. As VCAM-1 is an important mediator of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. As anticipated, bilirubin-treated animals manifested significantly less colonic injury and reduced infiltration of inflammatory cells into colon tissues. We further observed that bilirubin administration was associated with a reduced number of eosinophils and monocytes in the small intestine, with a corresponding increase in peripheral blood eosinophilia, regardless of whether mice received DSS. These findings suggest that bilirubin impairs the normal migration of eosinophils into intestinal tissues, as supported by experiments showing that bilirubin blocks the VCAM-1-dependent movement of Jurkat cells across human endothelial cell monolayers. Taken together, our findings support that bilirubin ameliorates DSS-induced colitis and disrupts the physiological trafficking of leukocytes to the intestine by preventing transmigration across the vascular endothelium, potentially through the inhibition VCAM-1-mediated signaling. Our findings raise the possibility that bilirubin functions as an endogenous regulator of inflammatory responses.
越来越多的证据表明，在血红素生理分解过程中产生的胆红素具有强大的抗炎作用。我们团队之前的研究表明，胆红素能够通过破坏血管细胞黏附分子-1（VCAM-1）依赖性细胞信号传导，阻止白细胞迁移到靶组织，从而抑制炎症反应。由于VCAM-1是葡聚糖硫酸钠（DSS）诱导的小鼠炎症性结肠炎组织损伤的重要介质，我们研究了胆红素是否能预防DSS处理小鼠的结肠损伤。正如预期的那样，接受胆红素治疗的动物结肠损伤明显减轻，炎症细胞向结肠组织的浸润减少。我们进一步观察到，无论小鼠是否接受DSS处理，给予胆红素后小肠中的嗜酸性粒细胞和单核细胞数量减少，外周血嗜酸性粒细胞增多。这些发现表明，胆红素损害了嗜酸性粒细胞向肠道组织的正常迁移，实验表明胆红素可阻断Jurkat细胞通过人内皮细胞单层的VCAM-1依赖性运动，支持了这一观点。综上所述，我们的研究结果支持胆红素可改善DSS诱导的结肠炎，并通过阻止白细胞跨血管内皮迁移，可能是通过抑制VCAM-1介导的信号传导，破坏白细胞向肠道的生理运输。我们的研究结果提出了胆红素作为炎症反应内源性调节因子的可能性。
