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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-04-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20442861/pdf/?tool=EBI |
| _version_ | 1818742826289070080 |
|---|---|
| author | Jan M Ehrchen Kirsten Roebrock Dirk Foell Nadine Nippe Esther von Stebut Johannes M Weiss Niels-Arne Münck Dorothee Viemann Georg Varga Carsten Müller-Tidow Hans-Joachim Schuberth Johannes Roth Cord Sunderkötter |
| author_facet | Jan M Ehrchen Kirsten Roebrock Dirk Foell Nadine Nippe Esther von Stebut Johannes M Weiss Niels-Arne Münck Dorothee Viemann Georg Varga Carsten Müller-Tidow Hans-Joachim Schuberth Johannes Roth Cord Sunderkötter |
| author_sort | Jan M Ehrchen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T02:18:41Z |
| format | Article |
| id | doaj.art-6493a6742fe44136a6161639025b50cd |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-18T02:18:41Z |
| publishDate | 2010-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-6493a6742fe44136a6161639025b50cd2022-12-21T21:24:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-04-0164e100087110.1371/journal.ppat.1000871Keratinocytes determine Th1 immunity during early experimental leishmaniasis.Jan M EhrchenKirsten RoebrockDirk FoellNadine NippeEsther von StebutJohannes M WeissNiels-Arne MünckDorothee ViemannGeorg VargaCarsten Müller-TidowHans-Joachim SchuberthJohannes RothCord SunderkötterExperimental 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20442861/pdf/?tool=EBI |
| spellingShingle | Jan M Ehrchen Kirsten Roebrock Dirk Foell Nadine Nippe Esther von Stebut Johannes M Weiss Niels-Arne Münck Dorothee Viemann Georg Varga Carsten Müller-Tidow Hans-Joachim Schuberth Johannes Roth Cord Sunderkötter Keratinocytes determine Th1 immunity during early experimental leishmaniasis. PLoS Pathogens |
| title | Keratinocytes determine Th1 immunity during early experimental leishmaniasis. |
| title_full | Keratinocytes determine Th1 immunity during early experimental leishmaniasis. |
| title_fullStr | Keratinocytes determine Th1 immunity during early experimental leishmaniasis. |
| title_full_unstemmed | Keratinocytes determine Th1 immunity during early experimental leishmaniasis. |
| title_short | Keratinocytes determine Th1 immunity during early experimental leishmaniasis. |
| title_sort | keratinocytes determine th1 immunity during early experimental leishmaniasis |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20442861/pdf/?tool=EBI |
| work_keys_str_mv | AT janmehrchen keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT kirstenroebrock keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT dirkfoell keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT nadinenippe keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT esthervonstebut keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT johannesmweiss keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT nielsarnemunck keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT dorotheeviemann keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT georgvarga keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT carstenmullertidow keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT hansjoachimschuberth keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT johannesroth keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis AT cordsunderkotter keratinocytesdetermineth1immunityduringearlyexperimentalleishmaniasis |