DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

Seidel, Petra; Goulet, Stéphanie; Hostettler, Katrin; Tamm, Michael; Roth, Michael

doi:10.1186/1465-9921-11-145

Cited by 36 publications

(31 citation statements)

References 34 publications

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“…Glutathione ethylester (GSH-OEt) was dissolved to a final concentration of 1 mM in serum-free medium. The cytotoxic efficacy of DMF concentrations was not significant, as reported previously [13].…”

Section: Drug Preparationsupporting

confidence: 85%

“…Previously, we reported that DMF significantly reduces the PDGF-BB-induced proliferation of ASMCs through induction of HO-1, suggesting that DMF may reduce airway remodelling [13]. In this study, we were interested in whether DMF-mediated up-regulation of HO-1 is also involved in DMF's anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 98%

“…In human ASMCs, we showed that DMF inhibited TNF-a-induced secretion of IL-6, eotaxin and RANTES (regulated on activation, T-cell expressed and secreted) [12]. Furthermore, we observed an inhibitory effect of DMF through HO-1 on platelet-derived growth factor (PDGF)-BB-induced ASMC proliferation [13]. These beneficial effects of DMF together with its clinical long-term safety profile make it an interesting drug for the therapy of chronic inflammatory lung diseases [14].…”

mentioning

confidence: 84%

“…Protein extracts were size-fractionated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and were transferred onto nitrocellulose membranes as described previously [13]. …”

Section: Immunoblottingmentioning

confidence: 99%

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Dimethylfumarate inhibits CXCL10 via haem oxygenase-1 in airway smooth muscle

Seidel

Hostettler²,

Hughes

et al. 2012

European Respiratory Journal

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CXCL10 stimulates mast cell infiltration into airway smooth muscle bundles and, thus, activate cytokine secretion and airway smooth muscle cell (ASMC) proliferation. Dimethylfumarate (DMF) reduces cytokine secretion by lymphocytes and ASMC proliferation through haem oxygenase (HO)-1. Therefore, we investigated the potency of DMF to inhibit tumour necrosis factor (TNF)-a-and interferon (IFN)-c-induced CXCL10 secretion by human ASMCs.Human primary ASMCs were pre-incubated with DMF and/or fluticasone and/or glutathione ethylester before cells were stimulated with IFN-c and/or TNF-a.DMF inhibited CXCL10 secretion and increased HO-1 levels, and p38 mitogen-activated protein kinase (MAPK) inhibition reduced DMF-dependent HO-1 expression. The DMF effect on CXCL10 secretion was abrogated by pre-treatment with HO-1 small interfering RNA (siRNA). Glutathione supplementation reversed all DMF effects on CXCL10 secretion and p38 MAPK phosphorylation. Importantly, combining DMF with fluticasone further reduced CXCL10 secretion. In addition, DMF inhibited IFN-c-induced CXCL10 secretion. This effect was compensated by glutathione supplementation or by pre-treatment with HO-1 siRNA. In addition, DMF reduced TNF-a-induced granulocyte colony-stimulating factor (G-CSF) secretion but had no effect on INF-c-induced G-CSF secretion.In human primary ASMCs, DMF inhibits CXCL10 secretion by reducing the cellular glutathione level and by activation of p38 MAPK and HO-1. Therefore, DMF may reduce airway inflammation in asthma by a glucocorticoid-independent pathway.

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Section: Drug Preparationsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 84%

“…Protein extracts were size-fractionated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and were transferred onto nitrocellulose membranes as described previously [13]. …”

Section: Immunoblottingmentioning

confidence: 99%

See 2 more Smart Citations

Dimethylfumarate inhibits CXCL10 via haem oxygenase-1 in airway smooth muscle

Seidel

Hostettler²,

Hughes

et al. 2012

European Respiratory Journal

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“…Recently, it has been demonstrated that a chemical that depletes GSH induced HO-1 by activation of p38 MAPK in airway smooth muscle cells (33). In addition, EP has also been shown to deplete GSH in LPS-stimulated RAW 264.7 cells (36).…”

Section: Ep Depletes Gsh and Activates P38 Mapk And Nrf2 In Lps-activmentioning

confidence: 99%

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Jang

Kim

Tsoyi

et al. 2012

Antioxidants & Redox Signaling

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Aims: We investigated the molecular mechanism by which ethyl pyruvate (EP) induces heme oxygenase-1 (HO-1) in RAW 264.7 cells and its effect on survival rate in cecal ligation and puncture (CLP)-induced wild-type (WT) and HO-1 knockout (HO-1 -/ -) septic mice. Results: EP induced HO-1 in a dose-and time-dependent manner, which was mediated through p38 mitogen-activated protein kinase (MAPK) and NF-E2-related factor 2 (Nrf2) signaling cascade in RAW 264.7 cells. EP significantly inhibited the lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS) expression and high-mobility group box 1 (HMGB1) release in RAW 264.7 cells. The inhibitory effect of EP on LPS-stimulated iNOS expression and HMGB1 release was reversed by transfection with siHO-1RNA in RAW 264.7 cells, but EP failed to reduce them in HO-1 -/ -peritoneal macrophages treated with LPS. Moreover, treatment of cells with glutathione ethyl ester (GSH-Et), SB203580 (p38 MAPK inhibitor), siHO-1, or p38-siRNA transfection inhibited anti-inflammatory effect of EP. Interestingly, both HO-1 induction and phosphorylation of p38 by EP were reversed by GSH-Et, and antioxidant redox elementluciferase activity by EP was reversed by SB203580 in LPS-activated cells. EP increased survival and decreased serum HMGB1 in CLP-WT mice, whereas it did not increase survival or decrease circulating HMGB1 in HO-1 -/ -CLP-mice. Innovation and Conclusion: Our work provides new insights into the understanding the molecular mechanism by showing that EP induces HO-1 through a p38 MAPK-and NRF2-dependent pathway by decreasing GSH cellular levels. We conclude that EP inhibits proinflammatory response to LPS in macrophages and increases survival in CLP-induced septic mice by upregulation of HO-1 level, in which p38 MAPK and Nrf2 play an important role. Antioxid. Redox Signal. 17, 878-889.

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Malabaricone C inhibits PDGF‐induced proliferation and migration of aortic smooth muscle cells through induction of heme oxygenase‐1

Lee

Seo

Ryoo

et al. 2012

J of Cellular Biochemistry

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Malabaricone C (Mal-C), isolated from nutmeg, is known to exert a variety of pharmacological activities. However, the effect of Mal-C on vascular smooth muscle cells (VSMCs) is unknown. This study examined the effect of Mal-C on proliferation and migration of primary rat aortic smooth muscle cells (RASMCs) as well as its underlying mechanisms. Treatment of RASMCs with Mal-C induced both protein and mRNA expression of heme oxygenase-1 (HO-1) in a dose- and time-dependent manner. Mal-C-mediated HO-1 induction was inhibited by treatment with actinomycin D or by cycloheximide. SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor), and N-acetylcysteine (NAC, an antioxidant) did not suppress Mal-C-induced HO-1 expression. In contrast, LY294002 (a PI3K inhibitor) blocked Mal-C-induced HO-1 expression. Moreover, RASMCs treated with Mal-C exhibited activation of AKT in a dose- and time-dependent manner. Treatment of RASMCs with Mal-C increased nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2), which is a key regulator of HO-1 expression, and this translocation was also inhibited by LY294002. Consistent with the notion that HO-1 has protective effects against VSMCs, Mal-C remarkably inhibited platelet-derived growth factor (PDGF)-induced proliferation and migration of RASMCs. However, inhibition of HO-1 significantly attenuated the inhibitory effects of Mal-C on PDGF-induced proliferation and migration of RASMCs. Taken together, these findings suggest that Mal-C could suppress PDGF-induced proliferation and migration of RASMCs through Nrf2 activation and subsequent HO-1 induction via the PI3K/AKT pathway, and may be a potential HO-1 inducer for preventing or treating vascular diseases.

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DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

Cited by 36 publications

References 34 publications

Dimethylfumarate inhibits CXCL10 via haem oxygenase-1 in airway smooth muscle

Dimethylfumarate inhibits CXCL10 via haem oxygenase-1 in airway smooth muscle

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Malabaricone C inhibits PDGF‐induced proliferation and migration of aortic smooth muscle cells through induction of heme oxygenase‐1

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