Phospholipase cε, an effector of ras and rap small GTPases, is required for airway inflammatory response in a mouse model of bronchial asthma

PLoS One. 2014 Sep 30;9(9):e108373. doi: 10.1371/journal.pone.0108373. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / enzymology*
  • Asthma / immunology
  • Asthma / pathology
  • Bronchi / enzymology*
  • Bronchi / immunology
  • Bronchi / pathology
  • Bronchial Hyperreactivity / chemically induced
  • Bronchial Hyperreactivity / enzymology*
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / pathology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation
  • Immunoglobulin E / blood
  • Immunoglobulin G / blood
  • Male
  • Mice
  • Mice, Knockout
  • Ovalbumin
  • Phosphoinositide Phospholipase C / deficiency
  • Phosphoinositide Phospholipase C / genetics
  • Phosphoinositide Phospholipase C / immunology*
  • Primary Cell Culture
  • Respiratory Mucosa / enzymology
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Th1-Th2 Balance / drug effects
  • Th2 Cells / drug effects
  • Th2 Cells / metabolism
  • Th2 Cells / pathology
  • Tumor Necrosis Factor-alpha / pharmacology
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / immunology
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / immunology


  • Immunoglobulin G
  • Tumor Necrosis Factor-alpha
  • ras GTPase-Activating Proteins
  • Immunoglobulin E
  • Ovalbumin
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon
  • rap GTP-Binding Proteins

Grant support

This work was supported by JSPS KAKENHI 23390071 and MEXT Global COE Program A08 to T.K., JSPS KAKENHI 24790810 to T.N., and JSPS KAKENHI 22790290 and 24590379 to H.E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.