Interleukin-23 is sufficient to induce rapid de novo legut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells

被引：126

作者：

Chan, I. H. ^{[1
]}

Jain, R. ^{[1
]}

Tessmer, M. S. ^{[1
]}

Gorman, D. ^{[1
]}

Mangadu, R. ^{[1
]}

Sathe, M. ^{[1
]}

Vives, F. ^{[1
]}

Moon, C. ^{[1
]}

Penaflor, E. ^{[1
]}

Turner, S. ^{[1
]}

Ayanoglu, G. ^{[1
]}

Chang, C. ^{[1
]}

Basham, B. ^{[1
]}

Mumm, J. B. ^{[1
]}

Pierce, R. H. ^{[1
]}

Yearley, J. H. ^{[1
]}

McClanahan, T. K. ^{[1
]}

Phillips, J. H. ^{[1
]}

Cua, D. J. ^{[1
]}

Bowman, E. P. ^{[1
]}

Kastelein, R. A. ^{[1
]}

LaFace, D. ^{[1
]}

机构：

[1] Merck Res Labs, Palo Alto, CA 94304 USA

来源：

MUCOSAL IMMUNOLOGY | 2014年 / 7卷 / 04期

关键词：

INFLAMMATORY-BOWEL-DISEASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; COLON-CANCER; TNF-ALPHA; IL-23; RECEPTOR; COLITIS; RISK; MECHANISMS;

D O I：

10.1038/mi.2013.101

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Chronic inflammation has been associated with increased risk for developing gastrointestinal cancer. Interleukin-23 (IL-23) receptor signaling has been correlated with inflammatory bowel disease pathogenesis, as well as promotion of tumor growth. However, little is known about the relative potential for IL-23-directed causality in gut tumorigenesis. We report that IL-23 transgene expression was sufficient to induce rapid (3-4 weeks) de novo development of intestinal adenomas with 100% incidence. Initiation of tumorigenesis was independent of exogenous carcinogens, Helicobacter colonization, or pre-existing tumor-suppressor gene mutations. Tumorigenesis was mediated by Thy1(+)IL-23R(+) innate lymphoid cells (ILC3), in part, through IL-17 responses as tumor development was inhibited in RAG(-/-) x IL-17(-/-) double knockout mice. Remarkably, IL-23 initiation of tumorigenesis by resident ILCs consistently occurred before recruitment of conspicuous inflammatory infiltrates. Our results reveal an explicit role for IL-23-mediated initiation of gut tumorigenesis and implicate a key role for IL-23R+ILC3 in the absence of overt cellular infiltrate recruitment.

引用

页码：842 / 856

页数：15

共 42 条

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