H-J Choi1, S-Y Park1, J H Cho1, J-W Park2, J-H Sohn2, Y-J Kim2, J-W Oh3, J-S Han1. 1. Biomedical Research Institute and Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea. 2. Department of Internal Medicine and Institute of Allergy, College of Medicine, Yonsei University, Seoul, Korea. 3. Department of Pediatrics, College of Medicine, Hanyang University, Seoul, Korea.
Abstract
BACKGROUND: House dust mites (HDMs) are the most important source of indoor aeroallergens that contribute to the rising incidence of allergic diseases such as allergic asthma. The major HDM, Der f 2, induces inflammatory cytokine expression. Little is known about the signaling pathway involved. OBJECTIVE: We wanted to define the Der f 2 signaling pathway from its receptor to the transcription factor responsible for IL-13 expression and production. METHODS: Human bronchial epithelial cells were stimulated with Der f 2. The release and gene expression of IL-13 were measured by means of ELISA and RT-PCR, respectively. In the airway inflammation mouse model, airway responses were assessed using ELISA, histology, BAL fluid, and methacholine responsiveness. RESULTS: Here, we show that Der f 2 binds to TLR4 and induces IL-13 expression and production. In the airway inflammation mouse model, Der f 2-induced IL-13 production significantly decreased with treatment of TAK-242, a novel TLR4 inhibitor. Activation of TLR4 by Der f 2 requires the recruitment and activation of Syk, which leads to phosphorylation of PLCγ and membrane translocation of PKCα. p38 MAPK is then activated by PKCα and stimulates PLD1 activity by phosphorylating the Thr147 residue of PLD1. PLD1 activation enhanced binding of ROCK1 to ATF-2 and leads to increased expression of IL-13. CONCLUSION: Our data extend the knowledge for a variety of possible roles of PLD1 in allergic disorders including asthma pathogenesis and suggest possible candidacy of PLD1 as a molecular target for novel therapeutic approaches.
BACKGROUND: House dust mites (HDMs) are the most important source of indoor aeroallergens that contribute to the rising incidence of allergic diseases such as allergic asthma. The major HDM, Der f 2, induces inflammatory cytokine expression. Little is known about the signaling pathway involved. OBJECTIVE: We wanted to define the Der f 2 signaling pathway from its receptor to the transcription factor responsible for IL-13 expression and production. METHODS:Human bronchial epithelial cells were stimulated with Der f 2. The release and gene expression of IL-13 were measured by means of ELISA and RT-PCR, respectively. In the airway inflammationmouse model, airway responses were assessed using ELISA, histology, BAL fluid, and methacholine responsiveness. RESULTS: Here, we show that Der f 2 binds to TLR4 and induces IL-13 expression and production. In the airway inflammationmouse model, Der f 2-induced IL-13 production significantly decreased with treatment of TAK-242, a novel TLR4 inhibitor. Activation of TLR4 by Der f 2 requires the recruitment and activation of Syk, which leads to phosphorylation of PLCγ and membrane translocation of PKCα. p38 MAPK is then activated by PKCα and stimulates PLD1 activity by phosphorylating the Thr147 residue of PLD1. PLD1 activation enhanced binding of ROCK1 to ATF-2 and leads to increased expression of IL-13. CONCLUSION: Our data extend the knowledge for a variety of possible roles of PLD1 in allergic disorders including asthma pathogenesis and suggest possible candidacy of PLD1 as a molecular target for novel therapeutic approaches.
Authors: Michael P Pelst; Clara Höbart; Charlotte Wallaeys; Hilde De Rooster; Yannick Gansemans; Filip Van Nieuwerburgh; Bert Devriendt; Eric Cox Journal: Front Immunol Date: 2020-06-09 Impact factor: 7.561
Authors: Meina Li; Christine R Keenan; Guillermo Lopez-Campos; Jonathan E Mangum; Qianyu Chen; Danica Prodanovic; Yuxiu C Xia; Shenna Y Langenbach; Trudi Harris; Vinzenz Hofferek; Gavin E Reid; Alastair G Stewart Journal: iScience Date: 2019-01-21