Dimethylfumarate inhibits CXCL10 via haem oxygenase-1 in airway smooth muscle.
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)-α- and interferon (IFN)-γ-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-γ and/or TNF-α. 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-γ-induced CXCL10 secretion. This effect was compensated by glutathione supplementation or by pre-treatment with HO-1 siRNA. In addition, DMF reduced TNF-α-induced granulocyte colony-stimulating factor (G-CSF) secretion but had no effect on INF-γ-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.
Dept of Biomedicine and Pneumology, Dept of Internal Medicine, University Hospital Basel, Basel,  Switzerland.
Petra
P
Seidel
Katrin E
KE
Hostettler
J Margaret
JM
Hughes
Michael
M
Tamm
Michael
M
Roth
D001980:Bronchi / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors*; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology
D054357:Chemokine CXCL10; D005650:Fumarates; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D000069462:Dimethyl Fumarate