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Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice
  1. Xiaoling Jin1,
  2. Teresa A Zimmers1,2,
  3. Zongxiu Zhang1,
  4. Robert H Pierce3,
  5. Leonidas G Koniaris1,2
  1. 1Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
  2. 2Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA
  3. 3Department of Pathology, University of Rochester School of Medicine, Rochester, New York, USA
  1. Correspondence to Dr Leonidas G Koniaris, Surgical Oncology, 3550 Sylvester Comprehensive Cancer Center (310T), 1475 NW 12th Ave, Miami, FL 33136, USA; lkoniaris{at}med.miami.edu

Abstract

Background and aims 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 ∼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.

  • Gut
  • bowel
  • necrosis
  • apoptosis
  • enterocyte
  • STAT3
  • colon cancer
  • proliferation

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Footnotes

  • See Editorial, p149

  • Funding This work was supported by National Institutes of Health grants NIH GM-6360301 and NIH NIDDK 62314, the Dewitt Daughtry Family Department of Surgery, the Sylvester Comprehensive Cancer Center, and the Papanicolaou Corps for Cancer Research (LGK).

  • Competing interests None.

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