title: Mitogen-activated protein kinase (MAPK) regulates leukotriene D4-induced HB-EGF and ADAM12 expression in human airway smooth muscle cells.
abstract: 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 LTD4 in HB-EGF and ADAM12 expression and the regulatory mechanism in human ASM cells, we analyzed a functioning signaling molecule in LTD4-induced HB-EGF and ADAM12 expression in human ASM cells by focusing on the role of mitogen-activated protein kinase (MAPK) cascades.
  
  
  METHODS
  Human ASM cells were stimulated LTD4 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 LTD4.
  
  
  RESULTS
  LTD4 induced an extracellular-signal regulated kinase (ERK), p38 MAPK and c-Jun-NH2-terminal kinase (JNK) phosphorylation in human ASM cells. LTD4 induced HB-EGF and ADAM12 mRNA expression. Furthermore, the regulation of LTD4-induced HB-EGF and ADAM12 mRNA expression is associated with ERK and p38 MAPK, not but JNK.
  
  
  CONCLUSIONS
  we conclude that p38 MAPK and ERK are capable of regulating LTD4-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.
authors.affiliation: Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Kumasawa
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takeshita
authors.forename: Akira
authors.initials: A
authors.lastname: Onose
authors.forename: Itsuro
authors.initials: I
authors.lastname: Jibiki
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Maruoka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072199:ADAM12 Protein; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D017998:Leukotriene D4 / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D012137:Respiratory System; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D017998:Leukotriene D4; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human