Interleukin-6 Is an Important In Vivo Inhibitor of Intestinal Epithelial Cell Death in Mice

Background & Aims: Interleukin-6 (IL-6) is a well-recognized mediator of liver disease and regeneration. However, the in vivo effects of IL-6 on enterocytes and the intestinal tract have not been elucidated. We sought to determine the in vivo effects of IL-6 on enterocytes. Methods: Murine models of increased or absent IL-6 were examined. Results: Systemic, high-dose IL-6 administration to mice over 7-10 days resulted in intestinal hyperplasia with a ~40% increase in small bowel mass and in intestinal villus height. No increase in crypt cell proliferation was noted. IL-6 administration was associated with induction of pSTAT3 in enterocytes along the lower and middle regions of villi but not in crypts. IL-6 administration was also associated with induction of anti-apoptotic proteins including pAKT, ref-1, and FLIP. along with decreased executor caspase activity and PARP cleavage. Pulse bromodeoxyuridine (BrdU) labeling demonstrated equivalent crypt cell proliferation rates but prolonged enterocyte lifespan and slowed enterocyte migration rates in IL-6 treated mice. Furthermore, IL-6–treated mice showed less intestinal injury and improved barrier function following ischemia reperfusion of the small bowel. Conversely, Il6 null mice exhibited impaired recovery following massive enterectomy and increased apoptosis after 5-fluorouracil chemotherapy relative to wild-type controls. Conclusions: IL-6 inhibited both constitutive and induced enterocyte cell death in vivo. Loss of IL-6 in mice resulted in increased activation of pro-apoptotic and necrotic pathways in enterocytes after injury. Therapies that augment IL-6 or its signaling pathways may help manage intestinal disorders associated with increased apoptosis, necrosis, and gut injury.