Gene Trap Mice Reveal an Essential Function of Dual Specificity Phosphatase Dusp16/MKP-7 in Perinatal Survival and Regulation of Toll-like Receptor (TLR)-induced Cytokine Production

Niedzielska, Magdalena; Bodendorfer, Barbara; Münch, Sandra; Eichner, Alexander; Derigs, Marcus; Costa, Olivia da; Schweizer, Astrid; Neff, Frauke; Nitschke, Lars; Sparwasser, Tim; Keyse, Stephen M.; Lang, Roland

doi:10.1074/jbc.m113.535245

Cited by 23 publications

(37 citation statements)

References 45 publications

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“…The results revealed embryonic lethality of Mkp7 2/2 mice with the majority of the KO mice dying between embryonic days 15.5 and 17.5 (Supplemental Fig. 2C), demonstrating that MKP7 is required for normal embryonic development in mice, which is similar to a recently published study (12).…”

Section: Mkp7 Deficiency Results In Embryonic Lethalitysupporting

confidence: 77%

“…The expression of Th17 lineage-specific genes including IL-17A, IL-17F, IL-21 and IL-22, and RORgt, the transcription factor essential for Th17 differentiation (12,16), were determined by quantitative RT-PCR. We found that the expression of Th17 lineage-specific genes and transcription factor was impaired in MKP7 KO Th17 cells compared with WT cells (Fig.…”

Section: Mkp7 Is Required For Th17 Differentiation and Effector Functmentioning

confidence: 99%

“…It has been shown that MKP7 binds to JNK scaffold proteins including JNK-interacting protein-1 and b-arrestin 2 to negatively regulate JNK activation (9,10). It was reported that MKP7 inhibits IL-12 and TNF-a production in macrophages in response to LPS stimulation (11,12). However, little is known on the physiological function of this protein in immune responses, especially in T cell responses in vivo.…”

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confidence: 99%

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MAPK Phosphatase 7 Regulates T Cell Differentiation via Inhibiting ERK-Mediated IL-2 Expression

Zhang

Nallaparaju

Liu

et al. 2015

The Journal of Immunology

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Members of the MAPK phosphatase (MKP) protein family play critical roles in immune responses through differential regulation of MAPK activation. In this study, we show that MKP7, also known as dual-specificity phosphatase 16, was required for CD4+ T cell responses in vivo. Mkp7−/− CD4+ T cells exhibited enhanced ERK and JNK activation, and produced increased amount of IL-2 compared with Mkp7+/+ cells upon activation. Mkp7−/− CD4+ T cells were selectively defective in Th17 differentiation in vitro, which was rescued by blocking IL-2 or inhibition of ERK activation. Furthermore, mice carrying Mkp7−/− T cells were deficient in generation of Th17 and T follicular helper cells in vivo, and were resistant to autoimmune experimental encephalomyelitis. Our results thus demonstrate an essential role of MKP7 in effector T cell function.

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Section: Mkp7 Deficiency Results In Embryonic Lethalitysupporting

confidence: 77%

Section: Mkp7 Is Required For Th17 Differentiation and Effector Functmentioning

confidence: 99%

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confidence: 99%

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MAPK Phosphatase 7 Regulates T Cell Differentiation via Inhibiting ERK-Mediated IL-2 Expression

Zhang

Nallaparaju

Liu

et al. 2015

The Journal of Immunology

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“…Several Dusp family members are highly inducible by MAPKactivating stimuli and act as negative feedback regulators. Examples with an established function in the immune system are Dusp1/MKP-1 (10-13), Dusp2/PAC1 (14), Dusp10/MKP-5 (15), and Dusp16/MKP-7 (16,17). Investigations in the respective knockout mice have shown that a lack of these inducible Dusp phosphatases leads to alterations in the patterns of cytokines produced via the effects of dysregulated MAPK activation (for review, see Refs.…”

Section: N Innate Immune Cells Recognition Of Microbial Ligands Bymentioning

confidence: 99%

Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-β Production

Niedzielska

Raffi

Tel

et al. 2015

The Journal of Immunology

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Plasmacytoid dendritic cells (pDCs) efficiently produce large amounts of type I IFN in response to TLR7 and TLR9 ligands, whereas conventional DCs (cDCs) predominantly secrete high levels of the cytokines IL-10 and IL-12. The molecular basis underlying this distinct phenotype is not well understood. In this study, we identified the MAPK phosphatase Dusp9/MKP-4 by transcriptome analysis as selectively expressed in pDCs, but not cDCs. We confirmed the constitutive expression of Dusp9 at the protein level in pDCs generated in vitro by culture with Flt3 ligand and ex vivo in sorted splenic pDCs. Dusp9 expression was low in B220− bone marrow precursors and was upregulated during pDC differentiation, concomitant with established pDC markers. Higher expression of Dusp9 in pDCs correlated with impaired phosphorylation of the MAPK ERK1/2 upon TLR9 stimulation. Notably, Dusp9 was not expressed at detectable levels in human pDCs, although these displayed similarly impaired activation of ERK1/2 MAPK compared with cDCs. Enforced retroviral expression of Dusp9 in mouse GM-CSF–induced cDCs increased the expression of TLR9-induced IL-12p40 and IFN-β, but not of IL-10. Conditional deletion of Dusp9 in pDCs was effectively achieved in Dusp9flox/flox; CD11c-Cre mice at the mRNA and protein levels. However, the lack of Dusp9 in pDC did not restore ERK1/2 activation after TLR9 stimulation and only weakly affected IFN-β and IL-12p40 production. Taken together, our results suggest that expression of Dusp9 is sufficient to impair ERK1/2 activation and enhance IFN-β expression. However, despite selective expression in pDCs, Dusp9 is not essential for high-level IFN-β production by these cells.

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“…ERK, JNK, p38) via dephosphorylation of phosphotyrosine and phosphothreonine residues, and thus play a key role in inflammation mediated diseases. Indeed various MKPs including MKP-1, MKP-5, MKP-7, MKP-x (DUSP22) and DUSP5 have been shown to be important in regulating immune responses123456. For example, MKP-1 negatively regulates the production of inflammatory cytokines TNF-α, IL-6 and IL-1β, and the anti-inflammatory IL-10789, as well as chemokines and other inflammatory mediators10111213.…”

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confidence: 99%

MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells

Barbour

Plevin

Jiang

2016

Sci Rep

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Mitogen-activated protein kinase phosphatases (MKPs) play key roles in inflammation and immune mediated diseases. Here we investigated the mechanisms by which MKP-2 modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). Our results show that MKP-2 mRNA levels in the spinal cord and lymphoid organs of EAE mice were increased compared with naive controls, indicating an important role for MKP-2 in EAE development. Indeed, MKP-2−/− mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4+ and CD8+ T cells in spleens and lymph nodes. In addition, MKP-2−/− CD11c+ dendritic cells (DCs) had reduced expression of MHC-II and CD40 compared with MKP-2+/+ mice. Subsequent experiments revealed that CD4+ T cells from naïve MKP-2−/− mice had decreased cell proliferation and IL-2 and IL-17 production relative to wild type controls. Furthermore, co-culture experiments showed that bone marrow derived DCs of MKP-2−/− mice had impaired capability in antigen presentation and T cell activation. While MKP-2 also modulates macrophage activation, our study suggests that MKP-2 is essential to the pathogenic response of EAE, and it acts mainly via regulating the important antigen presenting DC function and T cell activation.

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Gene Trap Mice Reveal an Essential Function of Dual Specificity Phosphatase Dusp16/MKP-7 in Perinatal Survival and Regulation of Toll-like Receptor (TLR)-induced Cytokine Production

Cited by 23 publications

References 45 publications

MAPK Phosphatase 7 Regulates T Cell Differentiation via Inhibiting ERK-Mediated IL-2 Expression

MAPK Phosphatase 7 Regulates T Cell Differentiation via Inhibiting ERK-Mediated IL-2 Expression

Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-β Production

MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells

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