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

Abstract

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.

Glomerular Epithelial Cells-Targeted Heme Oxygenase-1 Over Expression in the Rat: Attenuation of Proteinuria in Secondary But Not Primary Injury

“…The mechanism underlying the decrease in macrophage infiltration observed in glomeruli of anti-GBM Ab-treated GEC HO-1 rats is unknown. In this regard, it was previously reported that GEC can attract macrophages through the production and secretion of chemokines, as shown for the chemokine CXCL10 [31], while HO-1 negatively regulates CXCL10 [32]. …”

Anti-Inflammatory Dimethylfumarate: A Potential New Therapy for Asthma?

“…In addition, CXCL10 secretion by ASMC is sensitive to changes in cellular glutathione (GSH) levels [27], suggesting a link of this signaling pathway to the asthma-associated upregulation of mitochondria, which control the cellular redox system [42]. Interestingly, the thiazolidinedione ciglitazone strongly inhibited cytokine-induced CXCL10 protein without affecting CXCL10 mRNA level, suggesting that CXCL10 is regulated on the posttranslational level in ASMC [41].…”

“…NF- κ B activity was reported to be increased in the airways of asthmatic patients [97]. In addition, proinflammatory cytokines such as TNF- α activated NF- κ B in ASMC in vitro , which resulted in the secretion of a variety of proinflammatory factors including RANTES, CXCL10, or CCL11 [26, 27, 35]. In vitro, inhibition of NF- κ B downregulated the release of a range of proinflammatory mediators by ASMC [98].…”

“…Once activated, Nrf2 binds to the antioxidant response elements (AREs) within the promoter of antioxidant genes such as HO-1 initiating their transcription. DMF reduced intracellular-reduced GSH level and upregulated HO-1 in ASMC [27, 35]. HO-1 is an inducible enzyme, which protects the lungs from increased oxidative stress [107].…”

“…In addition, HO-1 protected the lungs against hyperoxic injury and attenuated allergen-induced airway inflammation and hyperreactivity in animal models of asthma [108, 109]. We demonstrated that DMF induced HO-1 and thereby inhibited PDGF-BB-induced ASMC proliferation and CXCL10 secretion [27, 36]. Importantly, DMF inhibited CXCL10 by ASMCs more efficiently when combined with the GC fluticasone, suggesting a GC sparing effect of DMF [27].…”