Pyrrolidine Dithiocarbamate Inhibits Interleukin-6 Signaling through Impaired STAT3 Activation and Association with Transcriptional Coactivators in Hepatocytes

He, Hua; Zhu, Tie Nian; Xie, Yi; Fan, Jinshui; Kole, S.D.P.; Saxena, Satya; Bernier, Michel

doi:10.1074/jbc.m603762200

Cited by 33 publications

(32 citation statements)

References 65 publications

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“…However, the precise mechanism by which PDTC inhibits NF-B activation remains controversial. Recent studies have shown that in some cell systems PDTC acts as an anti-inflammatory agent inhibiting IL-6-mediated STAT3 activation (20). In the present study, PDTC in a dose-dependent manner rescued endothelial cell membrane integrity as evidenced by reversal of MCTinduced destruction/degradation of plasmalemmal membrane proteins such as caveolin-1 and Tie2.…”

Section: Discussionsupporting

confidence: 53%

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Huang

Kaminski²,

Edwards³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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R. Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 294: L1250-L1259, 2008. First published April 4, 2008 doi:10.1152/ajplung.00069.2007.-Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1, and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF-B have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation, and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC; starting on days 1, 3, and 14 ϫ 2 wk), an inhibitor of inflammation and NF-B activation. Hemodynamic data, the expression of inhibitory (I)-B␣, caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF-B, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wk post-MCT. There was progressive reduction in the expression of caveolin-1, Tie2, and activation of PY-STAT3 in the lungs. Reduction in I-B␣ expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF-B activation were observed only at 2 wk post-MCT and both decreased by 4 wk post-MCT despite progressive PAH. PDTC (starting on days 1 and 3) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I-B␣ expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF-B activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-B activation appear to be a transient phenomenon in the MCT model. Thus the disruption of endothelial cell membrane integrity resulting in caveolin-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.caveolin-1; inhibitory B␣; inflammation; PY-STAT3; Tie2 DESPITE MAJOR ADVANCES MADE in the understanding of the pathogenesis of pulmonary artery hypertension (PAH), the precise molecular mechanism remains elusive. Both inflammation and oxidant stress have been implicated in the pathogenesis of PAH. Perivascular infiltration with inflammatory cells is evident in plexiform lesions in the lungs of patients with primary PAH, and the levels of proinflammatory cytokines such as IL-1 and IL-6 are elevated in the serum (22,47). In addition, the occurrence of PAH in patients suffering from systemic inflammatory diseases is not uncommon (14). Monocrotaline (MCT)-induced PAH in rats is preceded by an inflammatory response in the lungs and is associated with an early and progressive increase in the expression of IL-6 mRNA and IL-6 bioactivity in the lungs (6). IL-6 is known to activate STAT3, a transcription factor that positively regulates cell growth and proliferation. Tyrosine phosphorylation of STAT3 is required for STAT3 dimerization and subsequent translocation to nucleus where it binds with D...

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Section: Discussionsupporting

confidence: 53%

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Huang

Kaminski²,

Edwards³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Because of its ability to inhibit NF-B and the production of inflammatory cytokines (22,33), it is likely that PDTC preserves pancreatic ␤-cell mass and function through a decrease in intraislet inflammatory cytokine production (e.g., IL-1␤) in this HFD/STZ model. Studies have also shown that PDTC treatment reduces IL-6-mediated STAT3 activation and expression of acute-phase response proteins in HepG2 cells (13,42). This small thiol compound can also activate the transcription factor HSF1 and expression of target genes, many of which are involved in cellular protection against apoptosis (36).…”

Section: E414 Pdtc Action In Fat-fed Streptozotocin-treated Ratsmentioning

confidence: 99%

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Zhu

Zhang

Bernier

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC) on hepatic glycogen synthesis and FoxO1 transcriptional activity in type 2 diabetic rats and the mechanism underlying these effects. Fasting blood glucose and glycogen deposition, together with expressions of two key genes related to gluconeogenesis, were studied in the liver of rats fed a normal diet (NC), high-fat diet (HFD)-induced insulin-resistant rats made type 2 diabetic by a single intraperitoneal injection of streptozotocin (DM), and a DM with intervention of PDTC (DM + PDTC) for 1 wk. The phosphorylation of Akt, GSK-3β, and FoxO1 was assessed in liver extracts of fasted rats by Western blot, whereas indirect immunofluorescence staining was performed to determine the cellular distribution of FoxO1. The DM rats exhibited obvious increases in fasting blood glucose as well as decreased hepatic glycogen content compared with the NC group. Activation of the Akt/GSK-3β pathway and inactivating phosphorylation of FoxO1 were reduced greatly in DM rat livers ( P < 0.01). By contrast, PDTC treatment protected DM rats against high fasting blood glucose and hepatic glycogen deposition loss. PDTC also elicited an increase in Akt/GSK-3β signaling and subsequent inactivation and nuclear export of FoxO1 in DM rat livers, which translated into a significant reduction in the expression of two FoxO1 target genes, phospho enolpyruvate carboxykinase and glucose-6-phosphatase. This study suggests that PDTC enhances hepatic glycogen synthesis, whereas it reduces FoxO1 transcriptional activity in DM rats.

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“…NF-kB is typically localized to the cytoplasm as a p65 and p50 heterodimer. Activated NF-kB enters the nucleus and can promote the transcription of its target genes, including pro-inflammatory cytokine IL-6 and TNF-α (Snyder et al, 2002;He et al, 2006;Kim et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-κB pathway

Fei¹,

Zhu²,

Xia³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The dried roots of the plant Acanthopanax senticosus (AS) are used in traditional Oriental medicine and reportedly possess anti-inflammatory properties in vitro. However, whether AS has the same anti-inflammatory effect in vivo and the underlying mechanisms of this action remain unknown. In this study, we pretreated a mouse model of lipopolysaccharide-induced acute lung injury with AS and found that the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophils in bronchoalveolar lavage fluid were reduced and that inflammation in lung tissues was attenuated. To determine the mechanisms of these actions, we next assessed the effects of AS on the activation of the nuclear factor (NF)-kB pathway. We found that AS decreased the level of NF-kB and the DNA-binding activity of NF-kB. In summary, we found that AS attenuated the levels of TNF-α and IL-6 in the lung tissue of a mouse model of acute lung injury by inhibiting the NF-kB pathway.

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Pyrrolidine Dithiocarbamate Inhibits Interleukin-6 Signaling through Impaired STAT3 Activation and Association with Transcriptional Coactivators in Hepatocytes

Cited by 33 publications

References 65 publications

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-κB pathway

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