Neutrophil infiltration favors colitis-associated tumorigenesis by activating the interleukin-1 (IL-1)/IL-6 axis

• Published in: Mucosal immunology Vol. 7; no. 5; pp. 1106 - 1115
• Main Authors: Wang, Y, Wang, K, Han, G-C, Wang, R-X, Xiao, H, Hou, C-M, Guo, R-F, Dou, Y, Shen, B-F, Li, Y, Chen, G-J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2014; Elsevier Limited
• Subjects: 631/250/127/1213; 631/250/2504/223/1699; 692/420/755; 692/699/67/1504/1885; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Carcinogenesis - immunology; Colitis, Ulcerative - complications; Colitis, Ulcerative - immunology; Colonic Neoplasms - etiology; Disease Models, Animal; Flow Cytometry; Gastroenterology; Humans; Immunohistochemistry; Immunology; Interleukin-1 - metabolism; Interleukin-6 - metabolism; Mice; Mice, Nude; Neutrophil Infiltration - immunology; Polymerase Chain Reaction
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2013.126

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)-1β that is critical for the development of CAC. Depletion of neutrophil or blockade of IL-1β activity significantly reduced mucosal damage and tumor formation. This protumorigenic function of IL-1β 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-1β expression in neutrophils. Importantly, accumulation of IL-1β-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-1β-dependent manner. Overall, these findings reveal that in CAC milieu, infiltrating neutrophils secrete IL-1β that promotes tumorigenesis by inducing IL-6 production by intestinal MPs.