| MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. | |
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MedLine Citation:
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PMID: 21085614 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage. |
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Authors:
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Mashael S Al-Mutairi; Laurence C Cadalbert; H Adrienne McGachy; Muhannad Shweash; Juliane Schroeder; Magdalena Kurnik; Callum M Sloss; Clare E Bryant; James Alexander; Robin Plevin |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-11 |
Journal Detail:
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Title: PLoS pathogens Volume: 6 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-11-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101238921 Medline TA: PLoS Pathog Country: United States |
Other Details:
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Languages: eng Pagination: e1001192 Citation Subset: IM |
Affiliation:
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Division of Physiology & Pharmacology, Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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089273/Z/09/z//Wellcome Trust |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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