Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells
2013; Elsevier BV; Volume: 7; Issue: 4 Linguagem: Inglês
10.1038/mi.2013.101
ISSN1935-3456
AutoresIvan H. Chan, Renu Jain, Marlowe S. Tessmer, Dan Gorman, Ruban Mangadu, Manjiri Sathe, Francina Langa‐Vives, Christina Moon, E Penaflor, Scott Turner, Gulesi Ayanoglu, Chiung‐Hung Chang, Beth Basham, John B. Mumm, Robert H. Pierce, Jennifer H. Yearley, Terrill K. McClanahan, Joseph H. Phillips, D J, Edward P. Bowman, Rob Kastelein, Drake LaFace,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoChronic 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−/− × 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.
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