Increased inflammation and lethality of Dusp1−/− mice in polymicrobial peritonitis models

Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
Immunology (Impact Factor: 3.8). 11/2010; 131(3):395-404. DOI: 10.1111/j.1365-2567.2010.03313.x
Source: PubMed


The mitogen-activated protein kinase phosphatase Dusp1 (also known as MKP-1) is essential for control of the inflammatory response to systemic challenge with the lipopolysaccharide of Gram-negative bacteria. Here, we have investigated the consequences of Dusp1-deficiency in colon ascendens stent peritonitis (CASP) and caecal ligation and puncture (CLP), two mouse models of septic peritonitis. Following CASP, Dusp1(-/-) mice had increased serum levels of CCL4, interleukin-10 (IL-10) and IL-6, with differences from wild-type mice being dependent on severity of sepsis. These cytokines, along with inducible nitric oxide synthase messenger RNA, were also expressed at higher levels in spleen and liver. Similar over-production of these cytokines was detected in the CLP model, with even larger differences from wild-type mice. Despite the increased inflammatory response, bacterial clearance was impaired in Dusp1(-/-) mice subjected to CASP and CLP. Dusp1(-/-) mice suffered increased lethality in both peritonitis models. Together our data indicate that exaggerated inflammatory responses to gut bacteria introduced into the peritoneum in the absence of Dusp1 do not help to control bacterial replication but are detrimental for the host.

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Available from: Roland Lang, Oct 09, 2015
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    • "Dual-specificity phosphatases (DUSPs) or mitogen-activated protein kinase phosphatases (MKPs) are a subset of proteins, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases. For immune cells, DUSPs regulate responses in positive and negative ways and are key regulators of immune responses [18,19]. One of the external stimuli that activate DUSP1 gene expression is oxidative stress [20]. "
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    ABSTRACT: To quantitatively assess the superoxide dismutase 1 (SOD1), transforming growth factor, beta 1 (TGF-β1), and dual-specificity phosphatase 1 (DUSP1) messenger ribonucleic acid (mRNA) expression levels as the main intracellular reactive oxygen species neutralizers, wound healing mediators, and immunomodulators (respectively) in keratoconic (KCN) and non-KCN corneas. Total RNA was extracted from normal and keratoconic cultured corneal stromal fibroblasts. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to measure the relative expression levels of mRNAs of the SOD1, TGF-β1, and DUSP1 genes. The mRNA expression of TGF-β1 and DUSP1 was augmented in the KCN corneas (three- and fivefold, respectively; both p<0.05). The KCN and non-KCN samples showed no difference in comparative SOD1 mRNA levels. This study demonstrated a higher level of DUSP1 and TGF-β1 expression as known molecules in the inflammatory process. These results may provide new insight into the complex molecular pathways underlying KCN for investigating other inflammatory molecules.
    Molecular vision 12/2013; 19:2501-2507. · 1.99 Impact Factor
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    • "By binding to the GR, GCs modulate the immune response by transrepression (TR) of key inflammatory transcription factors, such as NFkB, and by transactivation (TA) of anti-inflammatory genes containing glucocorticoid responsive elements (GRE) (Ayroldi & Riccardi, 2009). For example, the prominent role of the GC-induced GRE-gene Dusp1 (encoding dual specific phosphatase 1) in the control of excessive inflammation has been confirmed in Dusp1 deficient mice, which are very sensitive for LPS and TNF-induced lethal inflammation (Vandevyver et al, 2012; Zhao et al, 2005) and in other sepsis models (Frazier et al, 2009; Hammer et al, 2010). Another important anti-inflammatory GRE gene is Tsc22d3 (TSC22 domain family member 3), also known as Gilz (glucocorticoidinduced leucine zipper) (D'Adamio et al, 1997). "
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    ABSTRACT: Natural variation for LPS-induced lethal inflammation in mice is useful for identifying new genes that regulate sepsis, which could form the basis for novel therapies for systemic inflammation in humans. Here we report that LPS resistance of the inbred mouse strain SPRET/Ei, previously reported to depend on the glucocorticoid receptor (GR), maps to the distal region of the X-chromosome. The GR-inducible gene Tsc22d3, encoding the protein Gilz and located in the critical region on the X-chromosome, showed a higher expressed SPRET/Ei allele, regulated in cis. Higher Gilz levels were causally related to reduced inflammation, as shown with knockdown and overexpression studies in macrophages. Transient overexpression of Gilz by hydrodynamic plasmid injection confirmed that Gilz protects mice against endotoxemia Our data strongly suggest that Gilz is responsible for the LPS resistance of SPRET/Ei mice and that it could become a treatment option for sepsis.
    EMBO Molecular Medicine 03/2013; 5(3). DOI:10.1002/emmm.201201683 · 8.67 Impact Factor
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    • "Similar enhanced inflammation has also been observed in DUSP10−/− mice following LPS challenge [76,77]. Interestingly, where live bacteria are used, the enhanced inflammation and supposedly stronger anti-bacterial immune response in DUSP1-deficient mice do not facilitate bacteria clearance, but instead cause a higher mortality rate [73] or increased bacteria burden [74,75]. These outcomes may be attributed to possible bacteria dissemination due to vascular injury [76] or to a novel function of IL-6 that enhances bacteria replication [74]. "
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    ABSTRACT: Phosphatases are important regulators of intracellular signaling events, and their functions have been implicated in many biological processes. Dual-specificity phosphatases (DUSPs), whose family currently contains 25 members, are phosphatases that can dephosphorylate both tyrosine and serine/threonine residues of their substrates. The archetypical DUSP, DUSP1/MKP1, was initially discovered to regulate the activities of MAP kinases by dephosphorylating the TXY motif in the kinase domain. However, although DUSPs were discovered more than a decade ago, only in the past few years have their various functions begun to be described. DUSPs can be categorized based on the presence or absence of a MAP kinase-interacting domain into typical DUSPs and atypical DUSPs, respectively. In this review, we discuss the current understanding of how the activities of typical DUSPs are regulated and how typical DUSPs can regulate the functions of their targets. We also summarize recent findings from several in vivo DUSP-deficient mouse models that studied the involvement of DUSPs during the development and functioning of T cells. Finally, we discuss briefly the potential roles of DUSPs in the regulation of non-MAP kinase targets, as well as in the modulation of tumorigenesis.
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