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

Mucosal Immunol. 2014 Jul;7(4):842-56. doi: 10.1038/mi.2013.101. Epub 2013 Nov 27.

Abstract

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(-/-) × 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / pathology
  • Animals
  • Carcinogens
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / immunology*
  • Cytokines / metabolism
  • Duodenum / metabolism
  • Duodenum / pathology
  • Gene Expression
  • Immunity, Innate*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-23 / genetics*
  • Interleukin-23 / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Lymphocyte Activation / immunology*
  • Lymphocytes / immunology*
  • Mice
  • Phenotype
  • Receptors, Interleukin / metabolism
  • Signal Transduction

Substances

  • Carcinogens
  • Cytokines
  • Interleukin-17
  • Interleukin-23
  • Receptors, Interleukin
  • interleukin-23 receptor, mouse
  • Interferon-gamma