title: Induction of interleukin 8 by American cockroach allergens from human airway epithelial cells via extracellular signal regulatory kinase and jun N-terminal kinase but not p38 mitogen-activated protein kinase.
abstract: BACKGROUND
  Cockroaches are potent aeroallergens associated with asthma. Several reports suggest that a novel group of G protein-linked receptors, protease-activated receptors (PARs), may be involved in the intracellular signaling pathway induced by aeroallergens of the epithelial cells.
  
  
  OBJECTIVE
  To investigate the mechanisms of American cockroach allergens (CraA) on interleukin 8 (IL-8) in human pulmonary epithelial cells.
  
  
  METHODS
  Protease activities of CraA were quantified by the Azocoll method. The gene and protein expressions of IL-8 from CraA-stimulated A549 cells were quantified by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The activity of different mitogen-activated protein kinases (MAPKs) was assessed by Western blot.
  
  
  RESULTS
  CraA-induced A549 cell IL-8 secretion in a dose-dependent manner at both the messenger RNA and protein levels. CraA-induced IL-8 secretion can be blocked by serine protease inhibitors, phenylmethane sulfonyl fluoride, and aprotinin but not by other protease inhibitors. Blocking antibodies against the cleavage sites of PAR-2 and PAR-3, but not of PAR-1, inhibited CraA-induced IL-8 production. CraA induced significant PAR-2 and PAR-3 messenger RNA upregulation and extracellular-regulated kinase (ERK/1/2) and Jun N-terminal kinase (JNK) phosphorylation but not p38 MAPK. Furthermore, ERK1/2 (U0126) and JNK (SP600125) inhibitors inhibited CraA-induced IL-8 secretion by 100% and 45%, respectively.
  
  
  CONCLUSIONS
  Both PAR-2 and PAR-3 might play a role in CraA-induced IL-8 secretion from human airway epithelial cells. It signals mainly through the ERK1/2 and partly from the JNK pathways. The key receptors and signaling molecules mediate cytokine release from the respiratory epithelium and can be potential therapeutic targets in treating cockroach allergy.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, and General Education Center, Overseas Chinese University, Taichung, Taiwan.
authors.forename: Mey-Fann
authors.initials: MF
authors.lastname: Lee
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Wang
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Liu
authors.forename: Shyh-Jye
authors.initials: SJ
authors.lastname: Lin
authors.forename: Yi-Hsing
authors.initials: YH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; D000818:Animals; D052179:Antigens, Plant / Q000302:isolation & purification / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins; D010526:Periplaneta / Q000276:immunology; D044463:Receptor, PAR-1 / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; D052179:Antigens, Plant; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D008565:Membrane Proteins; C509689:PARD3 protein, human; D044463:Receptor, PAR-1; C060835:allergen CRa, cockroach; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases