Distinct inflammatory mechanisms mediate early versus late colitis in mice

Gastroenterology. 2002 Jan;122(1):94-105. doi: 10.1053/gast.2002.30308.

Abstract

Background & aims: Progression from the acute to chronic phase of inflammatory bowel disease cannot be easily evaluated in patients and has not been characterized in animal models. We report a longitudinal study investigating changes in the mucosal immune response in an experimental model of colitis.

Methods: Severity of colitis, body mass, stool consistency and blood content, serum amyloid A, and tissue histology were examined in interleukin (IL)-10-deficient mice over 35 weeks. The corresponding production of IL-12, IL-18, interferon gamma, tumor necrosis factor alpha, IL-4, and IL-13 by lamina propria mononuclear cells in the inflamed intestine was measured. Administration of neutralizing antibody to IL-12 at distinct times during disease progression permitted evaluation of its therapeutic potential.

Results: The clinical manifestations and intestinal inflammation delineated an early phase of colitis (10-24 weeks), characterized by a progressive increase in disease severity, followed by a late phase (>25 weeks), in which chronic inflammation persisted indefinitely. Lamina propria mononuclear cells from mice with early disease synthesized progressively greater quantities of IL-12 and interferon gamma, whereas production of both cytokines dramatically declined and returned to pre-disease levels in the late phase of colitis. Consistent with this pattern, neutralizing antibody to IL-12 reversed early, but not late, disease. In contrast, IL-4 and IL-13 production increased progressively from pre- to early to late disease.

Conclusions: Colitis that develops in IL-10-deficient mice evolves into 2 distinct phases. IL-12 plays a pivotal role in early colitis, whereas its absence and the synthesis of IL-4 and IL-13 in late disease indicate that other immune mechanisms sustain chronic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies / pharmacology
  • Apolipoproteins / metabolism
  • Cells, Cultured
  • Chronic Disease
  • Colitis / immunology*
  • Colitis / metabolism
  • Diarrhea / immunology
  • Diarrhea / metabolism
  • Disease Models, Animal
  • Gastric Mucosa / immunology
  • Gastric Mucosa / metabolism
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-1 / biosynthesis
  • Interleukin-10 / genetics*
  • Interleukin-13 / biosynthesis
  • Interleukin-18 / genetics
  • Interleukin-18 / metabolism
  • Interleukin-4 / biosynthesis
  • Leukocytes / cytology
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Occult Blood
  • RNA, Messenger / analysis
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin-12
  • Serum Amyloid A Protein / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Antibodies
  • Apolipoproteins
  • Interleukin-1
  • Interleukin-13
  • Interleukin-18
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Serum Amyloid A Protein
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma