Phospholipase Cε, an Effector of Ras and Rap Small GTPases, Is Required for Airway Inflammatory Response in a Mouse Model of Bronchial Asthma

Background: Phospholipase C epsilon (PLC epsilon) is an effector of Ras and Rap small GTPases and expressed in non-immune cells. It is well established that PLC epsilon 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 PLC epsilon 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 PLC epsilon(+/+) mice and PLC epsilon(Delta X/Delta X) mutant mice in which PLC epsilon was catalytically-inactive. Mice with different PLC epsilon 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 hyperresponsiveness, bronchoalveolar lavage fluids, inflammatory cytokine levels, and OVA-specific immunoglobulin (Ig) levels. Effects of PLC epsilon genotype on cytokine production were also examined with primary-cultured bronchial epithelial cells. Results: After OVA challenge, the OVA-immunized PLC epsilon(Delta X/Delta X) mice exhibited substantially attenuated airway hyperresponsiveness 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 PLC epsilon genotype, suggesting that sensitization was PLC epsilon-independent. In the challenged mice, PLCe deficiency reduced proinflammatory cytokine production in the bronchial epithelial cells. Primary-cultured bronchial epithelial cells prepared from PLC epsilon(Delta X/Delta X) mice showed attenuated pro-inflammatory cytokine production when stimulated with tumor necrosis factor-alpha, suggesting that reduced cytokine production in PLC epsilon(Delta X/Delta X) mice was due to cell-autonomous effect of PLC epsilon deficiency. Conclusions: PLCe plays an important role in the pathogenesis of bronchial asthma through upregulating inflammatory cytokine production by the bronchial epithelial cells.