Urban particulate matter down-regulates filaggrin via COX2 expression/PGE2 production leading to skin barrier dysfunction.
We explored the regulation of filaggrin, cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) expression induced by urban particulate matter (PM) in human keratinocytes. In addition, we investigated the signaling pathways involved in PM-induced effects on COX2/PGE2 and filaggrin. PMs induced increases in COX2 expression and PGE2 production, and decreased filaggrin expression. These effects were attenuated by pretreatment with COX2 inhibitor and PGE2 receptor antagonist, or after transfection with siRNAs of the aryl hydrocarbon receptor (AhR), gp91phox and p47phox. Furthermore, PM-induced generation of reactive oxygen species (ROS) and NADPH oxidase activity was attenuated by pretreatment with an AhR antagonist (AhRI) or antioxidants. Moreover, Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38, and JNK, which then activated the downstream molecules NF-κB and AP-1, respectively. In vivo studies in PMs-treated mice showed that AhRI and apocynin (a Nox2 inhibitor) had anti-inflammatory effects by decreasing COX2 and increasing filaggrin expression. Our results reveal for the first time that PMs-induced ROS generation is mediated through the AhR/p47 phox/NADPH oxidase pathway, which in turn activates ERK1/2, p38/NF-κB and JNK/AP-1, and which ultimately induces COX2 expression and filaggrin downregulation. Up-regulated expression of COX2 and production of PGE2 may lead to impairment of skin barrier function.
Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan.|Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
Chiang-Wen
CW
Lee
Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.|Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.|School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Zih-Chan
ZC
Lin
Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Stephen Chu-Sung
SC
Hu
Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan.|School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
Yao-Chang
YC
Chiang
Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan.
Lee-Fen
LF
Hsu
Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan.|Department of Respiratory Care, Chang Gung University, Taoyuan, Taiwan.|Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Yu-Ching
YC
Lin
School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
I-Ta
IT
Lee
Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan.
Ming-Horng
MH
Tsai
Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.|Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Jia-You
JY
Fang
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000074662:NADPH Oxidase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects
D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D052638:Particulate Matter; D018336:Receptors, Aryl Hydrocarbon; D018078:Receptors, Prostaglandin E; D051546:Cyclooxygenase 2; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D015232:Dinoprostone