Mitogen-activated protein kinase (MAPK) regulates leukotriene D4-induced HB-EGF and ADAM12 expression in human airway smooth muscle cells.

Background: Cysteinyl leukotriene (LT) induces bronchoconstriction as well as airway inflammation and remodeling. Heparin-binding EGF-like growth factor (HB-EGF) is associated with remodeling in airway smooth muscle (ASM) cells in bronchial asthma. A disintegrin and metalloproteinase (ADAM) 12 is an enzyme implicated in the ectodomain shedding of membrane-anchored proHB-EGF and release of HB-EGF. Objective: To determine the role of LTD 4 in HB-EGF and ADAM12 expression and the regulatory mechanism in human ASM cells, we analyzed a functioning signaling molecule in LTD 4 -induced HB-EGF and ADAM12 expression in human ASM cells by focusing on the role of mitogen-activated protein kinase (MAPK) cascades. Method: Human ASM cells were stimulated LTD 4 in a time-dependent manner. We observed phosphorylation of MAPK by western blot analysis and the expression of HB-EGF and ADAM12 by quantitative PCR analysis of mRNA. Furthermore, we pretreated with specific inhibitors of MAPK and LTD 4 . Results: LTD 4 induced an extracellular-signal regulated kinase (ERK), p38 MAPK and c-Jun-NH 2 -terminal kinase (JNK) phosphorylation in human ASM cells. LTD 4 induced HB-EGF and ADAM12 mRNA expression. Furthermore, the regulation of LTD 4 -induced HB-EGF and ADAM12 mRNA expression is associated with ERK and p38 MAPK, not but JNK. Conclusion: we conclude that p38 MAPK and ERK are capable of regulating LTD 4 -induced HB-EGF and ADAM12 expression in human ASM cells. In bronchial asthma, the specific inhibitor of p38 MAPK and ERK may produce beneficial effects in controlling airway remodeling and inflammation.