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* Department of Dermatology, Johannes Gutenberg-University, Mainz,
Forschungszentrum Borstel, Germany;
Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan;
Department of Dermatology, Münster, Germany; and
¶ Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1
, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. Detailed analyses by Western blot and ELISA revealed that one-tenth of IL-12p40 detected in DC supernatants was released as the IL-12 antagonist IL-12p40 homodimer (IL-12p80). BALB/c DC released 
2-fold more IL-12p80 than C57BL/6 DC both in vitro and in vivo. Local injection of IL-12p80 during the first 3 days after infection resulted in increased lesion volumes for several weeks in both L. major-infected BALB/c or C57BL/6 mice, in higher lesional parasite burdens, and decreased Th1-cytokine production. Finally, IL-12p40-transgenic C57BL/6 mice characterized by overexpression of p40 showed increased levels of serum IL-12p80 and enhanced disease susceptibility. Thus, in addition to IL-1, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome.
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 This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 548 to E.v.S. and HO2145/2-1 to C.H.), the MAIFOR program of the University of Mainz (to E.v.S.), and the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (to M.C.U.).
2 A.P.N. and S.Z. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Esther von Stebut, Department of Dermatology, Johannes Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail address: vonstebu{at}mail.uni-mainz.de
4 Abbreviations used in this paper: DC, dendritic cell; Tg, transgenic; BMDC, bone marrow-derived DC; LN, lymph node.
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