title: Keratinocytes determine Th1 immunity during early experimental leishmaniasis.
abstract: Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1beta, osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen.
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ehrchen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Roebrock
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Nadine
authors.initials: N
authors.lastname: Nippe
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Niels-Arne
authors.initials: NA
authors.lastname: Münck
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schuberth
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology*; D007834:Lasers; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D042282:Microdissection; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000096:biosynthesis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D053495:Osteopontin; D018664:Interleukin-12; D015847:Interleukin-4