Sphingosylphosphorylcholine down-regulates filaggrin gene transcription through NOX5-based NADPH oxidase and cyclooxygenase-2 in human keratinocytes.
Sphingosylphosphorylcholine (SPC) mediates various inflammatory and behavioral responses in atopic dermatitis. Recent studies have shown that dysfunction of the epidermal permeability barrier itself plays a primary role in the etiology of atopic dermatitis. However, the effects of SPC on major proteins essential to the development of the epidermal permeability barrier such as filaggrin, loricrin, involucrin, keratin 1, keratin 10 and small proline-rich proteins are still unclear. In this study, we demonstrated that SPC significantly reduces filaggrin gene transcription, implying that SPC plays a pivotal role in impairment of the epidermal permeability barrier in atopic dermatitis lesional skin. In cultured normal human keratinocytes (NHKs), SPC increases the intracellular level of reactive oxygen species (ROS) and up-regulates NADPH oxidase 5 (NOX5) gene transcription. SPC also stimulates prostaglandin (PG) E(2) production by increasing cyclooxygenase (COX)-2 expression in NHK. The effects of the prostanoid EP receptor agonists, limaprost, butaprost, and sulprostone on filaggrin gene expression in NHK suggest that the prostanoid EP2 receptor plays a significant role in the PGE(2)-mediated filaggrin down-regulation. In contrast, limaprost and butaprost do not affect NOX5 expression in NHK, implying that the NOX5-regulated ROS pathway stimulated by SPC may be upstream of the COX-2 pathway. We propose that the increase in SPC levels further aggravates dermatological symptoms of atopic dermatitis through SPC-induced down-regulation of filaggrin in NHK.
Skin Research Institute, AmorePacific Corporation Research Center, Yongin, Gyeounggi-do 446-729, Republic of Korea.
Hyun
H
Choi
Shinhyoung
S
Kim
Hyoung-June
HJ
Kim
Kwang-Mi
KM
Kim
Chang-Hoon
CH
Lee
Jennifer H
JH
Shin
Minsoo
M
Noh
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D051546:Cyclooxygenase 2; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human; D013110:Sphingosine