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J Interferon Cytokine Res. 2018 Oct;38(10):445-451. doi: 10.1089/jir.2017.0134.

Interleukin-1 Signaling Mediates Obesity-Promoted Elevations in Inflammatory Cytokines, Wnt Activation, and Epithelial Proliferation in the Mouse Colon.

Author information

1
1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.
2
2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts.
3
3 Comparative Biology Unit, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University , Boston, Massachusetts.
4
4 Department of Gastroenterology, Tufts University School of Medicine , Boston, Massachusetts.

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-1β (IL-1β), a proinflammatory 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-1β in mediating some of the early biochemical and molecular events leading up to obesity-promoted CRC. Twenty-five wild-type (WT) C57BL/6J mice and 24 lacking a functional IL-1 receptor (IL1R-/-) 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-1β and tumor necrosis factor-α (TNF-α) in the colonic mucosa (IL-1β: P = 0.04; TNF-α: P < 0.05), activation of the Wnt signaling cascade [evidenced by a 2-fold increase in colonic crypt cells displaying intranuclear β-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 IL1R-/- mice. In the absence of IL-1 signaling, obesity-induced elevations of colonic IL-1β, TNF-α, 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 procancerous effects of obesity in the colon, thereby identifying a potential target for future strategies aimed at chemoprevention.

KEYWORDS:

IL-1β; TNFα; Wnt; obesity; proliferation

PMID:
30328795
DOI:
10.1089/jir.2017.0134

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