DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1.
BACKGROUND
Airway wall remodelling is an important pathology of asthma. Growth factor induced airway smooth muscle cell (ASMC) proliferation is thought to be the major cause of airway wall thickening in asthma. Earlier we reported that Dimethylfumarate (DMF) inhibits platelet-derived growth factor (PDGF)-BB induced mitogen and stress activated kinase (MSK)-1 and CREB activity as well as IL-6 secretion by ASMC. In addition, DMF altered intracellular glutathione levels and thereby reduced proliferation of other cell types.


METHODS
We investigated the effect of DMF on PDGF-BB induced ASMC proliferation, on mitogen activated protein kinase (MAPK) activation; and on heme oxygenase (HO)-1 expression. ASMC were pre-incubated for 1 hour with DMF and/or glutathione ethylester (GSH-OEt), SB203580, hemin, cobalt-protoporphyrin (CoPP), or siRNA specific to HO-1 before stimulation with PDGF-BB (10 ng/ml).


RESULTS
PDGF-BB induced ASMC proliferation was inhibited in a dose-dependant manner by DMF. PDGF-BB induced the phosphorylation of ERK1/2 and p38 MAPK, but not of JNK. DMF enhanced the PDGF-BB induced phosphorylation of p38 MAPK and there by up-regulated the expression of HO-1. HO-1 induction inhibited the proliferative effect of PDGF-BB. HO-1 expression was reversed by GSH-OEt, or p38 MAPK inhibition, or HO-1 siRNA, which all reversed the anti-proliferative effect of DMF.


CONCLUSIONS
Our data indicate that DMF inhibits ASMC proliferation by reducing the intracellular GSH level with subsequent activation of p38 MAPK and induction of HO-1. Thus, DMF might reduce ASMC and airway remodelling processes in asthma.
Seidel
Petra
P
Pulmonary Cell Research, University Hospital Basel, Switzerland.
Goulet
Stephanie
S
Hostettler
Katrin
K
Tamm
Michael
M
Roth
Michael
M
D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology; D000077214:Becaplermin; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005650:Fumarates / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis
D005650:Fumarates; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D051547:Heme Oxygenase-1; D000069462:Dimethyl Fumarate