Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice.
OBJECTIVE
Interleukin-6 (IL-6) is a well-recognised 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 approximately 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, and FLIP along with decreased executor caspase activity and PARP cleavage. Pulse bromodeoxyuridine labelling 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 ischaemia 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 signalling pathways may help manage intestinal disorders associated with increased apoptosis, necrosis and gut injury.
Jin
Xiaoling
X
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Zimmers
Teresa A
TA
Zhang
Zongxiu
Z
Pierce
Robert H
RH
Koniaris
Leonidas G
LG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D020895:Enterocytes / Q000166:cytology / Q000187:drug effects*; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D015850:Interleukin-6 / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D007421:Intestine, Small / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control; D050796:STAT3 Transcription Factor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse