Evidence for the critical role of interleukin-12 but not interferon-gamma in the pathogenesis of experimental colitis in mice.
OBJECTIVE
The imbalance between helper T (Th)1/Th2 cytokines has been observed in human inflammatory bowel disease and various animal models. Because interleukin (IL)-12 and interferon-gamma (IFN-gamma) productions are known to be a hallmark of Th1-dominant intestinal inflammation such as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we strictly addressed the roles of IFN-gamma and IL-12 in the development of colitis, employing knockout mice with IFN-gamma receptor (IFN-gammaR) or IL-12 p40 gene disruptions and mice administered with neutralizing monoclonal antibodies (mAbs) against IFN-gamma or IL-12.


METHODS
To induce colitis, 2.5 mg of the hapten reagent TNBS in 50% ethanol was administered into the colon. Two milligrams of rat anti-mouse IFN-gamma mAb, rat anti-mouse IL-12 mAb, or control rat IgG were administered intraperitoneally into mice before TNBS administration. Change in the body weight of mice was evaluated and the degree of inflammation of the colon of these mice was investigated histologically. Immunohistochemical and immunofluorescence analyses were performed to detect CD4+ T cells, macrophages and IL-12 in TNBS-induced colitis lesions. The profile of Th1 and Th2 cytokine expressions in colonic tissues was examined by cytokine-specific semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Single rectal administration of TNBS developed significant colitis in IFN-R-/- mice and anti-IFN-gamma mAb-pretreated mice, as well as control wild-type mice. Conversely, administration of TNBS produced no signs of colitis in IL-12 p40-/- and anti-IL-12 mAb-pretreated mice.


CONCLUSIONS
IL-12, but not IFN-gamma, plays a pivotal role in the pathogenesis of TNBS-induced colitis.
Tozawa
Kotaro
K
First Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Hanai
Hiroyuki
H
Sugimoto
Ken
K
Baba
Satoshi
S
Sugimura
Haruhiko
H
Aoshi
Taiki
T
Uchijima
Masato
M
Nagata
Toshi
T
Koide
Yukio
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D017471:Receptors, Interferon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D007371:Interferon-gamma; D018664:Interleukin-12; D012333:RNA, Messenger; D017471:Receptors, Interferon; D014302:Trinitrobenzenesulfonic Acid; D000096743:Interferon gamma Receptor