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CUTTING EDGE |
* Laboratory of Immunology, First Medical Clinic, University of Mainz, Mainz, Germany;
Institute of Pathology, University of Lausanne, Lausanne, Switzerland; and
Regeneron Pharmaceuticals, Tarrytown, NY 10591
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The work of M.F.N. was supported by the collaborative research grant SFB548.
2 Address correspondence and reprint requests to Dr. Markus F. Neurath, Laboratory of Immunology, I. Medical Clinic, University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. E-mail address: neurath{at}1-med.klinik.uni-mainz.de
3 Abbreviations used in this paper: DSS, dextran sodium sulfate; BMDC, bone marrow dendritic cell; LPMC, lamina propria mononuclear cell; gal, galactosidase; MEICS, murine endoscopic index of colitis severity.
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