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.