Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease

Gastroenterology. 2001 Oct;121(4):875-88. doi: 10.1053/gast.2001.28021.


Background & aims: Crohn's disease (CD) is associated with an increased number of infiltrating macrophages, which release a variety of proinflammatory cytokines. Interleukin (IL)-18 has been implicated in the modulation of mucosal CD4(+) T cells towards Th1 responses, which are implicated in the pathogenesis of CD. Here we assess the role of macrophages and of IL-18 in the murine model of intestinal inflammation that mimics the immunologic characteristics of human CD.

Methods: Colitis was induced in C57BL/6 mice immunized with 2,4,6-trinitrobenzene sulfonic acid (TNBS) followed by rectal administration of TNBS in ethanol. Mice were treated with either an antibody directed against macrophages conjugated to the ribosome-inactivating protein saporin (anti-Mac-1-saporin) or with a neutralizing antibody against IL-18. In addition, we assessed whether an identical TNBS immunization/challenge protocol could induce colitis in IL-18(-/-) mice.

Results: The colonic mucosa of TNBS-treated mice was marked by infiltration of Mac-1-positive macrophages and up-regulation of IL-18. The administration of the anti-Mac-1-saporin antibody or the neutralizing anti-IL-18 antibody resulted in a dramatic attenuation of mucosal inflammation in this model. In addition, TNBS was unable to induce significant colitis in the IL-18(-/-) mice.

Conclusions: Our data underscore the pivotal role of macrophages, and the macrophage-derived IL-18, in the establishment of TNBS-induced colitis in mice. Our results highlight the potential use of therapy directed against IL-18 in the treatment of patients with CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Colitis / immunology
  • Colitis / pathology
  • Colitis / prevention & control
  • Crohn Disease / immunology
  • Crohn Disease / physiopathology*
  • Disease Models, Animal
  • Humans
  • Inflammation / immunology*
  • Inflammation / physiopathology
  • Interleukin-18 / deficiency
  • Interleukin-18 / genetics
  • Interleukin-18 / physiology*
  • Intestinal Mucosa / immunology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Trinitrobenzenesulfonic Acid


  • Antibodies
  • Interleukin-18
  • Trinitrobenzenesulfonic Acid