Distinct inflammatory mechanisms mediate early versus late colitis in mice.
OBJECTIVE
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.
Spencer
David M
DM
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA.
Veldman
Geertruida M
GM
Banerjee
Subhashis
S
Willis
Joseph
J
Levine
Alan D
AD
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001053:Apolipoproteins / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D003967:Diarrhea / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics*; D018793:Interleukin-13 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009780:Occult Blood; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000276:immunology; D053707:Receptors, Interleukin-12; D000685:Serum Amyloid A Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000906:Antibodies; D001053:Apolipoproteins; D007375:Interleukin-1; D018793:Interleukin-13; D020382:Interleukin-18; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma