title: Phospholipase cε, an effector of ras and rap small GTPases, is required for airway inflammatory response in a mouse model of bronchial asthma.
abstract: BACKGROUND
  Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases and expressed in non-immune cells. It is well established that PLCε plays an important role in skin inflammation, such as that elicited by phorbol ester painting or ultraviolet irradiation and contact dermatitis that is mediated by T helper (Th) 1 cells, through upregulating inflammatory cytokine production by keratinocytes and dermal fibroblasts. However, little is known about whether PLCε is involved in regulation of inflammation in the respiratory system, such as Th2-cells-mediated allergic asthma.
  
  
  METHODS
  We prepared a mouse model of allergic asthma using PLCε+/+ mice and PLCεΔX/ΔX mutant mice in which PLCε was catalytically-inactive. Mice with different PLCε genotypes were immunized with ovalbumin (OVA) followed by the challenge with an OVA-containing aerosol to induce asthmatic response, which was assessed by analyzing airway hyper-responsiveness, bronchoalveolar lavage fluids, inflammatory cytokine levels, and OVA-specific immunoglobulin (Ig) levels. Effects of PLCε genotype on cytokine production were also examined with primary-cultured bronchial epithelial cells.
  
  
  RESULTS
  After OVA challenge, the OVA-immunized PLCεΔX/ΔX mice exhibited substantially attenuated airway hyper-responsiveness and broncial inflammation, which were accompanied by reduced Th2 cytokine content in the bronchoalveolar lavage fluids. In contrast, the serum levels of OVA-specific IgGs and IgE were not affected by the PLCε genotype, suggesting that sensitization was PLCε-independent. In the challenged mice, PLCε deficiency reduced proinflammatory cytokine production in the bronchial epithelial cells. Primary-cultured bronchial epithelial cells prepared from PLCεΔX/ΔX mice showed attenuated pro-inflammatory cytokine production when stimulated with tumor necrosis factor-α, suggesting that reduced cytokine production in PLCεΔX/ΔX mice was due to cell-autonomous effect of PLCε deficiency.
  
  
  CONCLUSIONS
  PLCε plays an important role in the pathogenesis of bronchial asthma through upregulating inflammatory cytokine production by the bronchial epithelial cells.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Edamatsu
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takenaka
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Sasaki
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001980:Bronchi / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin; D054801:Phosphoinositide Phospholipase C / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D058408:Th1-Th2 Balance / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D020703:ras GTPase-Activating Proteins; D007073:Immunoglobulin E; D010047:Ovalbumin; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D020668:rap GTP-Binding Proteins