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Cutting Edge: IL-23 Cross-Regulates IL-12 Production in T Cell-Dependent Experimental Colitis

2006; American Association of Immunologists; Volume: 177; Issue: 5 Linguagem: Inglês

10.4049/jimmunol.177.5.2760

1550-6606

Christoph Becker, Heike Dornhoff, Clemens Neufert, Massimo Claudio Fantini, Stefan Wirtz, Sabine Huebner, Alexei Nikolaev, Hans‐Anton Lehr, Andrew Murphy, David M. Valenzuela, George D. Yancopoulos, Peter R. Galle, Margaret Karow, Markus F. Neurath,

T-cell and B-cell Immunology

Abstract Although IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.