Keratinocytes determine Th1 immunity during early experimental leishmaniasis.
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.
Ehrchen
Jan M
JM
Institute of Immunology, University of Muenster, Muenster, Germany.
Roebrock
Kirsten
K
Foell
Dirk
D
Nippe
Nadine
N
von Stebut
Esther
E
Weiss
Johannes M
JM
Münck
Niels-Arne
NA
Viemann
Dorothee
D
Varga
Georg
G
Müller-Tidow
Carsten
C
Schuberth
Hans-Joachim
HJ
Roth
Johannes
J
Sunderkötter
Cord
C
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
D053583:Interleukin-1beta; D015850:Interleukin-6; D053495:Osteopontin; D018664:Interleukin-12; D015847:Interleukin-4