Journal
MUCOSAL IMMUNOLOGY
Volume 7, Issue 5, Pages 1106-1115Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2013.126
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Funding
- National Key Basic Research Program of China [2013CB530506]
- National Natural Science Foundation of China [81272320, 81072475]
- Beijing Natural Science Foundation [7132151]
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Neutrophil infiltration is a key event in chronic intestinal inflammation and associated colorectal cancer, but how these cells support cancer development is poorly understood. In this study, using a mouse model of colitis-associated cancer (CAC), we have demonstrated that infiltrated neutrophils produce large amounts of interleukin-1 (IL)-1 beta that is critical for the development of CAC. Depletion of neutrophil or blockade of IL-1 beta activity significantly reduced mucosal damage and tumor formation. This protumorigenic function of IL-1 beta was mainly attributed to increased IL-6 secretion by intestine-resident mononuclear phagocytes (MPs). Furthermore, commensal flora-derived lipopolysaccharide (LPS) was identified to trigger IL-1 beta expression in neutrophils. Importantly, accumulation of IL-1 beta-expressing neutrophils was seen in lesions of patients suffering from ulceratic CAC and these infiltrated neutrophils induced IL-6 production by intestinal MPs in an IL-1 beta-dependent manner. Overall, these findings reveal that in CAC milieu, infiltrating neutrophils secrete IL-1 beta that promotes tumorigenesis by inducing IL-6 production by intestinal MPs.
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