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T Cell Hypo-Responsiveness against Leishmania major in MAP Kinase Phosphatase (MKP) 2 Deficient C57BL/6 Mice Does Not Alter the Healer Disease Phenotype.
In: PLoS Neglected Tropical Diseases, Jg. 7 (2013-02-21), Heft 2, S. 1-11
Online
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Zugriff:
We have recently demonstrated that MAP kinase phosphatase 2 (MKP-2) deficient C57BL/6 mice, unlike their wild-type counterparts, are unable to control infection with the protozoan parasite Leishmania mexicana. Increased susceptibility was associated with elevated Arginase-1 levels and reduced iNOS activity in macrophages as well as a diminished TH1 response. By contrast, in the present study footpad infection of MKP-2−/− mice with L. major resulted in a healing response as measured by lesion size and parasite numbers similar to infected MKP-2+/+ mice. Analysis of immune responses following infection demonstrated a reduced TH1 response in MKP-2−/− mice with lower parasite specific serum IgG2b levels, a lower frequency of IFN-γ and TNF-α producing CD4+ and CD8+ T cells and lower antigen stimulated spleen cell IFN-γ production than their wild-type counterparts. However, infected MKP-2−/− mice also had similarly reduced levels of antigen induced spleen and lymph node cell IL-4 production compared with MKP-2+/+ mice as well as reduced levels of parasite-specific IgG1 in the serum, indicating a general T cell hypo-responsiveness. Consequently the overall TH1/TH2 balance was unaltered in MKP-2−/− compared with wild-type mice. Although non-stimulated MKP-2−/− macrophages were more permissive to L. major growth than macrophages from MKP-2+/+ mice, reflecting their reduced iNOS and increased Arginase-1 expression, LPS/IFN-γ activation was equally effective at controlling parasite growth in MKP-2−/− and MKP-2+/+ macrophages. Consequently, in the absence of any switch in the TH1/TH2 balance in MKP-2−/− mice, no significant change in disease phenotype was observed. Author Summary: Leishmania species are parasites that are of extensive public health importance in the tropics and subtropics. Within humans the parasites are intracellular and reside particularly within macrophages. Classical activation of macrophages by Interferon-γ (IFN-γ) induces the enzyme nitric oxide synthase (iNOS) and parasites are killed via the production of nitric oxide (NO) from the substrate L-arginine. Alternative activation by Interleukin-4 (IL-4) results in Arginase-1 expression, which depletes L-arginine and facilitates parasite growth. We have recently shown that MAP Kinase Phosphatase-2 (MKP-2) suppresses macrophage Arginase-1 and that C57BL/6 mice with a deletion of this gene are subsequently extremely susceptible to New World cutaneous leishmaniasis caused by Leishmania mexicana. Surprisingly, MKP-2 deficient mice have been shown here to be resistant to Old World cutaneous leishmaniasis caused by L. major. We show that during infection with L. major, enhanced Arginase-1 in MKP-2 deficient mice serves to induce a generalized T cell hypo-responsiveness so that IFN-γ and IL-4 levels are equally suppressed compared with intact mice. In addition, unlike L. mexicana, classically activated MKP-2 deficient macrophages were able to control L. major growth equally as well as MKP-2 intact macrophages, highlighting a fundamental difference in the control of these two species. [ABSTRACT FROM AUTHOR]
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T Cell Hypo-Responsiveness against Leishmania major in MAP Kinase Phosphatase (MKP) 2 Deficient C57BL/6 Mice Does Not Alter the Healer Disease Phenotype.
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Autor/in / Beteiligte Person: | Schroeder, Juliane ; McGachy, H. Adrienne ; Woods, Stuart ; Plevin, Robin ; Alexander, James |
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Zeitschrift: | PLoS Neglected Tropical Diseases, Jg. 7 (2013-02-21), Heft 2, S. 1-11 |
Veröffentlichung: | 2013 |
Medientyp: | academicJournal |
ISSN: | 1935-2727 (print) |
DOI: | 10.1371/journal.pntd.0002064 |
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