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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.

ABSTRACT: 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 T(H)1 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 T(H)1 response in MKP-2(-/-) mice with lower parasite specific serum IgG2b levels, a lower frequency of IFN-? and TNF-? producing CD4(+) and CD8(+) T cells and lower antigen stimulated spleen cell IFN-? 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 T(H)1/T(H)2 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-? activation was equally effective at controlling parasite growth in MKP-2(-/-) and MKP-2(+/+) macrophages. Consequently, in the absence of any switch in the T(H)1/T(H)2 balance in MKP-2(-/-) mice, no significant change in disease phenotype was observed.

SUBMITTER: Schroeder J

PROVIDER: S-EPMC3578781 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. METHODS:We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. RESULTS:Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. CONCLUSIONS:Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.

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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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