title: Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice.
abstract: 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-1alphabeta, 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 approximately 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-1alphabeta, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome.
authors.affiliation: Department of Dermatology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Axel P
authors.initials: AP
authors.lastname: Nigg
authors.forename: Sabine
authors.initials: S
authors.lastname: Zahn
authors.forename: Dominik
authors.initials: D
authors.lastname: Rückerl
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ehrchen
authors.forename: Florian
authors.initials: F
authors.lastname: Wölbing
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D019281:Dimerization; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism / Q000502:physiology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity
chemical_list: C513581:IL-12 p80, mouse; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12; D015847:Interleukin-4