Contrasting roles of IL-12p40 and IL-12p35 in the development of hapten-induced colitis.
IL-12(p70), a heterodimer composed of two subunits (p35 and p40), is a key cytokine for Th1 mediated inflammatory responses. We dissected the role of IL-12 in the development of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis by studying mice deficient in IL-12p40, IL-12p35, or IL-12Rbeta1. TNBS-treated IL-12Rbeta1(-/-) and IL-12p35(-/-) mice developed only a mild disease associated with low level IL-18 expression in IL-12p35(-/-) mice. In contrast, IL-12p40(-/-) mice developed more severe colitis than wild-type mice associated with high level colonic IL-18 expression. Administration of IL-12p40 neutralizing mononuclear antibody dramatically increased pathology in IL-12p35(-/-) mice similar to disease scored in IL-12p40(-/-) mice. Numbers of IFN-gamma-producing cells infiltrating the lamina propria were comparably augmented in the different groups of IL-12-mutant and wild-type mice. These results demonstrate that IL-12p40, in contrast to IL-12p70, inhibits TNBS-induced colitis and IL-18 expression independent of IFN-gamma.
Camoglio
Luisa
L
Department of Experimental Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. l.camoglio@amc.uva.nl
Juffermans
Nicole P
NP
Peppelenbosch
Maikel
M
te Velde
Anje A
AA
ten Kate
Fibo J
FJ
van Deventer
Sander J H
SJ
Kopf
Manfred
M
D000818:Animals; D001485:Basement Membrane / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006241:Haptens / Q000009:adverse effects; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D020382:Interleukin-18 / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12; D013601:T-Lymphocytes / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
D006241:Haptens; D020382:Interleukin-18; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid