Dual Specificity Phosphatase 1 Knockout Mice Show Enhanced Susceptibility to Anaphylaxis but Are Sensitive to Glucocorticoids

Maier, Jana V.; Brema, Susanne; Tuckermann, Jan; Herzer, Ute; Klein, Matthias; Stassen, Michael; Moorthy, Anbalagan; Cato, Andrew C. B.

doi:10.1210/me.2007-0067

Cited by 74 publications

(58 citation statements)

References 25 publications

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“…S8). Dexamethasone also inhibited TLR-stimulated cytokine production in DCs from control mice, consistent with reports in other cell types (27), but, similar to its effect on P-p38, here inhibition was only partially dependent on MKP-1 (Fig. 5).…”

Section: Mkp-1 Is Essential For Anti-ac Igm-mediated Suppression Of Isupporting

confidence: 89%

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

Grönwall

Chen

Vas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Naturally arising IgM antibodies, which recognize neo-determinants on apoptotic cell (AC) membranes, are present from birth and can be further induced by AC challenge. Such naturally arising IgM antibodies can suppress proinflammatory responses to purified agonists for Toll-like receptors (TLRs), as well as block the induction of IgG immune complex-induced in vitro and in vivo pathogenic responses. To investigate the responsible mechanisms, we studied the regulatory effects of IgM anti-AC antibody on responses in bone marrow-derived dendritic cells mediated by a range of different TLRs and found that addition of IgM anti-AC inhibited the activation of the primary MAPKs: ERK1/2, JNK, and particularly p38. This was dependent on the recruitment of either C1q or mannose-binding lectin, which are both early complement factors that tag ACs for innate immune recognition. Strikingly, MAPK inhibition of responses to TLR agonists, and to lupus IgG autoantibody-chromatin immune complexes, was found to correlate with, and had an absolute requirement for, the induction and nuclear localization of MAPK phosphatase-1, a factor known to mediate glucocorticoid suppression of immune responses. Further experiments showed that natural IgM antibodies in serum exhibited the same inhibitory properties. These studies elucidate a novel homeostatic pathway by which natural antibodies, which are products of the adaptive immune system, can directly blunt inflammatory responses by recruitment and coordination of a primitive regulatory pathway of the innate immune system. apoptotic cell | autoimmunity | Dusp-1 | inflammation | MBL

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Section: Mkp-1 Is Essential For Anti-ac Igm-mediated Suppression Of Isupporting

confidence: 89%

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

Grönwall

Chen

Vas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…GCs might have some direct antiinflammatory effects, or they might also act via the induction of other antiinflammatory proteins. This idea is supported by the prior finding that inhibition of protein synthesis in bone marrow-derived mast cells from Mkp1 -/-mice partly reverses the antiinflammatory effects of GCs (41).…”

Section: (E and F)mentioning

confidence: 54%

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Vandevyver¹,

Dejager²,

Bogaert³

et al. 2012

J. Clin. Invest.

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125

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Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation.Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1 -/-mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1 -/-mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1 -/-mice showed no change in sensitivity to TNF, Jnk2 -/-mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1 -/-and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.

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“…Other investigators reported increased mortality in Mkp-1 null mice challenged with Gram-positive bacterial infection, through the inactivation of JNK and p38 (56). Mkp-1 null mice have shown enhanced susceptibility to anaphylaxis, while maintaining sensitivity to glucocorticoids in bone marrow-derived mast cells from the same mice (32). However, MKP-1 in EC was presented as a novel and crucial mediator of the anti-inflammatory action of glucocorticoids (16).…”

Section: Discussionmentioning

confidence: 99%

Histone H3 as a novel substrate for MAP kinase phosphatase-1

Kinney

Chandrasekharan

Yang

et al. 2009

American Journal of Physiology-Cell Physiology

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Kinney CM, Chandrasekharan UM, Yang L, Shen J, Kinter M, McDermott MS, DiCorleto PE. Histone H3 as a novel substrate for MAP kinase phosphatase-1. Am J Physiol Cell Physiol 296: C242-C249, 2009. First published November 19, 2008 doi:10.1152/ajpcell.00492.2008.-Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a nuclear, dual-specificity phosphatase that has been shown to dephosphorylate MAP kinases. We used a "substrate-trap" technique involving a mutation in MKP-1 of the catalytically critical cysteine to a serine residue ("CS" mutant) to capture novel MKP-1 substrates. We transfected the MKP-1 (CS) mutant and control (wild-type, WT) constructs into phorbol 12-myristate 13-acetate (PMA)-activated COS-1 cells. MKP-1-substrate complexes were immunoprecipitated, which yielded four bands of 17, 15, 14, and 10 kDa with the CS MKP-1 mutant but not the WT MKP-1. The bands were identified by mass spectrometry as histones H3, H2B, H2A, and H4, respectively. Histone H3 was phosphorylated, and purified MKP-1 dephosphorylated histone H3 (phospho-Ser-10) in vitro; whereas, histone H3 (phospho-Thr-3) was unaffected. We have previously shown that thrombin and vascular endothelial growth factor (VEGF) upregulated MKP-1 in human endothelial cells (EC). We now show that both thrombin and VEGF caused dephosphorylation of histone H3 (phospho-Ser-10) and histone H3 (phospho-Thr-3) in EC with kinetics consistent with MKP-1 induction. Furthermore, MKP-1-specific small interfering RNA (siRNA) prevented VEGF-and thrombin-induced H3 (phospho-Ser-10) dephosphorylation but had no effect on H3 (phospho-Thr-3 or Thr-11) dephosphorylation. In summary, histone H3 is a novel substrate of MKP-1, and VEGF-and thrombin-induced H3 (phospho-Ser-10) dephosphorylation requires MKP-1. We propose that MKP-1-mediated H3 (phospho-Ser-10) dephosphorylation is a key regulatory step in EC activation by VEGF and thrombin.

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Dual Specificity Phosphatase 1 Knockout Mice Show Enhanced Susceptibility to Anaphylaxis but Are Sensitive to Glucocorticoids

Cited by 74 publications

References 25 publications

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Histone H3 as a novel substrate for MAP kinase phosphatase-1

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