title: Kaempferol Inhibits Endoplasmic Reticulum Stress-Associated Mucus Hypersecretion in Airway Epithelial Cells And Ovalbumin-Sensitized Mice.
abstract: Mucus hypersecretion is an important pathological feature of chronic airway diseases, such as asthma and pulmonary diseases. MUC5AC is a major component of the mucus matrix forming family of mucins in the airways. The initiation of endoplasmic reticulum (ER)-mediated stress responses contributes to the pathogenesis of airway diseases. The present study investigated that ER stress was responsible for airway mucus production and this effect was blocked by the flavonoid kaempferol. Oral administration of ≥10 mg/kg kaempferol suppressed mucus secretion and goblet cell hyperplasia observed in the bronchial airway and lung of BALB/c mice sensitized with ovalbumin (OVA). TGF-β and tunicamycin promoted MUC5AC induction after 72 h in human bronchial airway epithelial BEAS-2B cells, which was dampened by 20 μM kaempferol. Kaempferol inhibited tunicamycin-induced ER stress of airway epithelial cells through disturbing the activation of the ER transmembrane sensor ATF6 and IRE1α. Additionally, this compound demoted the induction of ER chaperones such as GRP78 and HSP70 and the splicing of XBP-1 mRNA by tunicamycin. The in vivo study further revealed that kaempferol attenuated the induction of XBP-1 and IRE1α in epithelial tissues of OVA-challenged mice. TGF-β and tunicamycin induced TRAF2 with JNK activation and such induction was deterred by kaempferol. The inhibition of JNK activation encumbered the XBP-1 mRNA splicing and MUC5AC induction by tunicamycin and TGF-β. These results demonstrate that kaempferol alleviated asthmatic mucus hypersecretion through blocking bronchial epithelial ER stress via the inhibition of IRE1α-TRAF2-JNK activation. Therefore, kaempferol may be a potential therapeutic agent targeting mucus hypersecretion-associated pulmonary diseases.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Sin-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Gong
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Yean-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Kang
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Yun-Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D000818:Animals; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007114:Immunization; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D044949:Kaempferols / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009093:Mucus / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D044949:Kaempferols; D047992:TNF Receptor-Associated Factor 2; D016212:Transforming Growth Factor beta; C006552:kaempferol; D010047:Ovalbumin; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases