Apoptosis signal-regulating kinase 1 in leukotriene D(4)-induced activator protein-1 activation in airway smooth muscle cells.
Cysteinyl leukotrienes (LTs) are involved in allergic disorders including bronchial asthma. Transcription factor activator protein-1 (AP-1) activation is essential for cell proliferation and differentiation. LTD(4) is shown to promote human airway smooth muscle cell proliferation; however, the effect of LTD(4) on AP-1 activation in airway smooth muscle cells and the molecular mechanism in regulating AP-1 activation have not been determined. We examined the effect LTD(4) on AP-1 activation in human airway smooth muscle cells and analyzed a role of apoptosis signal-regulating kinase1 (ASK1), an upstream kinase kinase of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in LTD(4)-induced AP-1 activation to clarify the signaling molecule regulating AP-1 activation. The results showed that LTD(4) induced AP-1 activation determined by AP-1-dependent luciferase gene activity and ASK1 phosphorylation. Transient transfection of the dominant negative form of ASK1 attenuated LTD(4)-induced AP-1 activation. In addition, LTD(4)-induced AP-1 activity was depressed in the dominant negative form of ASK1-stably transfected porcine artery endothelial cells compared to that in the parental porcine artery endothelial cells. These results indicate that LTD(4) is capable of inducing AP-1 activation and ASK1 regulates AP-1 activation in LTD(4)-stimulated airway smooth muscle cells.
Kumasawa
Fumio
F
Division of Respiratory Medicine, Department of Internal Medicine Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Hashimoto
Shu
S
Onose
Akira
A
Jibiki
Itsuro
I
Mizumura
Kenji
K
Matsumoto
Ken
K
Maruoka
Shuichiro
S
Gon
Yasuhiro
Y
Kobayashi
Tomoko
T
Takahashi
Noriaki
N
Ichijo
Hidenori
H
Horie
Takashi
T
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D020024:Leukotriene Antagonists; D011422:Propionates; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; C059141:verlukast; D017998:Leukotriene D4; D008156:Luciferases; D048848:MAP Kinase Kinase Kinase 5