MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana

Abstract

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 PGE2 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.

Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation

“…DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22). DUSP4 (also named MKP2) suppresses CD4 + T cell proliferation but induces normal Th1/Th2 responses following KLH immunization (23), whereas DUSP4 enhances Th1 responses following Leishmania mexicana infection (21). To our knowledge, our study demonstrates for the first time a novel immune function for DUSP14 in T cells in vivo.…”

“…Only two DUSPs (DUSP4 and DUSP10) are reported to be involved in T cell activation and T cell-mediated immune responses using KO mice (21)(22)(23). DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22).…”

Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Impairs Synaptic Plasticity and Hippocampal-Dependent Memory

“…Heterozygote MKP-2 mice backcrossed on a C57BL/6J background generated homozygous and wild-type littermates that were used for breeding colonies (Al-Mutairi et al, 2010). All breeding and experimentation were in accordance with UK legislation [Animals (Scientific Procedures) Act 1986] and with approval by the University of Strathclyde Ethics Committee.…”

16α, 17α-epoxypregnenolone-20-oxime inhibits NO and IL-6 production in LPS-treated RAW264.7 cells

“…The MAPK and NF-κB signaling pathways are crucial mediators of proinflammatory cytokine production in macrophages (9)(10)(11)(12). To determine the mechanism underlying the anti-inflammatory activities of EPREGO in RAW264.7 cells, the MAPK pathways were investigated by detecting the phosphorylation levels of ERK, JNK and p38.…”

“…In macrophages, the MAPK signaling pathway is one of the most extensively investigated intracellular signaling cascades involved in the LPS-induced inflammatory response (5)(6)(7)(8). The MAPK pathway is comprised of at least three signaling components: Extracellular signal-regulated kinases 1/2 (ERK 1/2); c-Jun N-terminal kinase (JNK); and p38 MAPK, all of which have been demonstrated to induce the release of immune-related cytotoxic factors and proinflammatory cytokines (9)(10)(11). Furthermore, NF-κB is important for controlling innate and adaptive immunity, and for regulating the expression of various genes during the inflammatory response (12 Activated NF-κB translocates into the nucleus of the cell and interacts with κB-binding sites in the promoter regions of target genes, in order to regulate the transcription of proinflammatory genes, including inducible nitric oxide synthase (iNOS), TNF-α and IL-6 (13,14).…”