Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #359357
Title: Interleukin-1 signaling mediates obesity-promoted elevations in inflammatory cytokines, Wnt activation, and epithelial proliferation in the mouse colon

Author
item PFALZER, ANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GARCIA, PALOMA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Interferon and Cytokine Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/20/2018
Publication Date: 10/1/2018
Citation: Pfalzer, A.C., Crott, J.W., Koh, G., Smith, D.E., Garcia, P.E., Mason, J.B. 2018. Interleukin-1 signaling mediates obesity-promoted elevations in inflammatory cytokines, Wnt activation, and epithelial proliferation in the mouse colon. Journal of Interferon and Cytokine Research. 38(10):445-451. https://doi.org/10.1089/jir.2017.0134.
DOI: https://doi.org/10.1089/jir.2017.0134

Interpretive Summary: Obesity increases the risk of developing colorectal cancer, and one means it appears to do so is by producing an inflammatory environment in the lining of the colon. One of several body chemicals that creates this inflammatory environment is a protein called interleukin-1 beta. We sought to understand how critical a role this particular inflammatory protein plays in enhancing cancer risk. By utilizing a genetically-altered mouse that lacks the IL-1beta pathway and making it obese, we showed that IL-1beta is instrumental in creating this inflammatory environment in the colon. The import of this observation, in part, is that strategies to block this protein can feasibly be targeted in order to block obesity's promotion of cancer risk.

Technical Abstract: Obesity is a prominent risk factor for colorectal cancer (CRC). One mechanism by which obesity promotes the development of CRC is by generating a chronic, low-grade state of colonic inflammation. Interleukin-1B, a pro-inflammatory cytokine often elevated in obesity, is known to activate several procarcinogenic signaling pathways that are implicated in colonic carcinogenesis. We therefore sought to define the role of IL-1beta in mediating some of the early biochemical and molecular events leading up to obesity-promoted CRC. Twenty-five wild-type C57BL/6J (WT) mice and 24 lacking a functional IL-1 receptor (IL1RKO) were each randomized to either low-fat or high-fat diets, resulting in lean and obese mice. Compared to WT lean controls, WT obese mice displayed 30-80% greater concentrations of IL-1beta and TNF-alpha in the colonic mucosa (IL-1beta: p=0.04; TNF-alpha: p<0.05), activation of the Wnt signaling cascade (evidenced by a two-fold increase in colonic crypt cells displaying intranuclear beta-catenin [p<0.03]), and a significant expansion of the proliferation zone of the colonic crypt (p<0.04). These obesity-induced alterations in colonic cytokines, Wnt signaling, and proliferation were absent in the obese IL1RKO mice. Conclusions: In the absence of interleukin-1 signaling, obesity-induced elevations of colonic IL-1beta, TNF-alpha, Wnt activation, and enhanced epithelial proliferation no longer occur. These observations underscore the important mechanistic roles that IL-1 signaling appears to play in mediating the pro-cancerous effects of obesity in the colon, thereby identifying a potential target for future strategies aimed at chemoprevention.