c-Jun N-Terminal Kinase Is Involved in Mercuric Ions-Mediated Interleukin-4 Secretion in Mast Cells

Walczak‐Drzewiecka, Aurelia; Wyczółkowska, J; Dastych, Jarosław

doi:10.1159/000083892

Cited by 11 publications

(5 citation statements)

References 66 publications

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“…Murine mast cell line and mouse bone marrow-derived cultured mast cells showed increase in histamine and cytokines, such as IL-4, IL-6 and tumor necrosis factor-alpha (TNF-α) along with vascular endothelial growth factor (VEGF). These observations are consistent with disruption of the blood-brain-barrier and consequent brain inflammation, as suggested by Walczak-Drzewiecka et al (2005), most likely via the activation of c-Jun N-terminal kinase (JNK).…”

Section: Discussionsupporting

confidence: 85%

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

et al. 2012

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Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal rat primary astrocytes. Astrocytes were pretreated for 66 hours with 5µg/ml IIIM1 (4.95 µM) followed by 6 hour exposure to MeHg (5 µM). MeHg significantly increased F2-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E2 (PGE2), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.

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Section: Discussionsupporting

confidence: 85%

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

et al. 2012

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“…are able to induce MAPKs activities and subsequently AP-1 activity [29,44,45]. A cross-talk between the AhR and AP-1 signaling pathways has been previously reported [14,46].…”

Section: +mentioning

confidence: 71%

NF‐κB and AP‐1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper

Korashy

El‐Kadi

2008

J Biochem & Molecular Tox

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We have previously shown that Hg(2+), Pb(2+), and Cu(2+), significantly modulate the expression of NAD(P):quinone oxidoreductase 1 (Nqo1) in Hepa 1c1c7 cells through oxidative stress-dependent mechanisms. In the current study, we examined the role of redox-sensitive transcription factors, NF-kappaB and AP-1 signaling pathways in the modulation of Nqo1 by heavy metals. Our results show that the depletion of cellular GSH using L-buthionine-(S,R)-sulfoximine further potentiated the heavy metal-mediated induction of Nqo1 at the mRNA and activity levels. The NF-kappaB activator, PMA, significantly abolished the metal-mediated effects on Nqo1 mRNA and activity. In parallel, the NF-kappaB inhibitor, PDTC, further potentiated the Pb(2+)- and Hg(2+)-mediated induction of Nqo1 mRNA and activity levels, respectively. Inhibition of AP-1 upstream signaling pathway such as JNK by SP600125 significantly suppressed heavy metal-mediated induction of Nqo1 mRNA and activity levels. In contrast, inhibition of ERK by U0126 further potentiated heavy metal-mediated effects on Nqo1 mRNA, while only potentiated Hg(2+)-mediated induction of Nqo1 activity. Furthermore, p38 MAPK inhibitor, SB203580 further potentiated Pb(2+)- and Cu(2+)-mediated effects at the mRNA levels, whereas did not alter the activity levels. These results clearly demonstrate that activation of NF-kappaB negatively regulates the expression of Nqo1 by heavy metals, whereas AP-1 signaling pathways differentially modulates the heavy metal-mediated effects.

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“…Cell lysates were produced as previously described (26). Briefly, cells were lysed on ice for 30 min in a buffer containing 50 mM Tris-HCl (pH 8.0), 1% nonionic detergent IGEPAL CA-630, 20 mM EDTA, 150 mM NaCl, 1 mM MgCl 2 , 10 mM tetrasodium pyrophosphate, 100 mM sodium fluoride, 2 mM sodium orthovanadate, 10 g/ml leupeptin, 10 g/ml aprotinin, and 1 mM PMSF.…”

Section: Preparation Of Cell Lysates Cytosolic Fractions and Nucleamentioning

confidence: 99%

HIF-1α Is Up-Regulated in Activated Mast Cells by a Process That Involves Calcineurin and NFAT

Walczak‐Drzewiecka

Ratajewski

Wagner

et al. 2008

The Journal of Immunology

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Mast cells play important roles in many pathological conditions where local hypoxia is observed, including asthma, rheumatic diseases, and certain types of cancer. Here, we investigated how expression of the hypoxia-inducible factor 1, α subunit gene (HIF1A), is regulated in mast cells. The product of HIF1A is hypoxia-inducible factor 1α (HIF-1α), is a major nuclear transcription factor modulating gene expression in response to hypoxic conditions. We observed that under hypoxic conditions, exposure of mast cells to ionomycin and substance P resulted in significant up-regulation of HIF1A expression as compared with resting mast cells incubated under identical conditions. The ionomycin-mediated increase in HIF-1α protein levels was sensitive to the transcription inhibitor actinomycin D and to inhibitors of calcineurin, cyclosporin A (CsA), and FK506. The increased HIF-1α protein level was paralleled by a severalfold increase in HIF-1α mRNA that could be also inhibited with actinomycin D and CsA. The HIF1A promoter activity was significantly increased in ionomycin-activated mast cells, and the promoter activity could be inhibited by CsA and FK506. Furthermore, in situ mutagenesis experiments showed that the ionomycin-mediated HIF1A promoter activity depends on a conservative NFAT-binding site. Thus, accumulation of HIF-1α in activated mast cells requires up-regulation of HIF1A gene transcription and depends on the calcineurin-NFAT signaling pathway.

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c-Jun N-Terminal Kinase Is Involved in Mercuric Ions-Mediated Interleukin-4 Secretion in Mast Cells

Cited by 11 publications

References 66 publications

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

NF‐κB and AP‐1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper

HIF-1α Is Up-Regulated in Activated Mast Cells by a Process That Involves Calcineurin and NFAT

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