title: 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.
abstract: MAPK activity is negatively regulated by members of the dual specificity phosphatase (Dusp) family, which differ in expression, substrate specificity, and subcellular localization. Here, we investigated the function of Dusp16/MKP-7 in the innate immune system. The Dusp16 isoforms A1 and B1 were inducibly expressed in macrophages and dendritic cells following Toll-like receptor stimulation. A gene trap approach was used to generate Dusp16-deficient mice. Homozygous Dusp16tp/tp mice developed without gross abnormalities but died perinatally. Fetal liver cells from Dusp16tp/tp embryos efficiently reconstituted the lymphoid and myeloid compartments with Dusp16-deficient hematopoietic cells. However, GM-CSF-induced proliferation of bone marrow progenitors in vitro was impaired in the absence of Dusp16. In vivo challenge with Escherichia coli LPS triggered higher production of IL-12p40 in mice with a Dusp16-deficient immune system. In vitro, Dusp16-deficient macrophages, but not dendritic cells, selectively overexpressed a subset of TLR-induced genes, including the cytokine IL-12. Dusp16-deficient fibroblasts showed enhanced activation of p38 and JNK MAPKs. In macrophages, pharmacological inhibition and siRNA knockdown of JNK1/2 normalized IL-12p40 secretion. Production of IL-10 and its inhibitory effect on IL-12 production were unaltered in Dusp16tp/tp macrophages. Altogether, the Dusp16 gene trap mouse model identifies an essential role in perinatal survival and reveals selective control of differentiation and cytokine production of myeloid cells by the MAPK phosphatase Dusp16.
authors: From the Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors: Magdalena
authors: M
authors: Niedzielska
authors: Barbara
authors: B
authors: Bodendorfer
authors: Sandra
authors: S
authors: Münch
authors: Alexander
authors: A
authors: Eichner
authors: Marcus
authors: M
authors: Derigs
authors: Olivia
authors: O
authors: da Costa
authors: Astrid
authors: A
authors: Schweizer
authors: Frauke
authors: F
authors: Neff
authors: Lars
authors: L
authors: Nitschke
authors: Tim
authors: T
authors: Sparwasser
authors: Stephen M
authors: SM
authors: Keyse
authors: Roland
authors: R
authors: Lang
mesh_terms: D000818:Animals; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D048049:Extracellular Signal-Regulated MAP Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C438002:Dusp16 protein, mouse
keywords: Cytokines/Interferon; Dendritic Cells; Dual Specificity Phosphatase; Endotoxin; Gene Knock-out; Gene Trap; Innate Immunity; MAP Kinases (MAPKs); Macrophages; Perinatal Lethality