TY - JOUR
T1 - Sphingosylphosphorylcholine down-regulates filaggrin gene transcription through NOX5-based NADPH oxidase and cyclooxygenase-2 in human keratinocytes
AU - Choi, Hyun
AU - Kim, Shinhyoung
AU - Kim, Hyoung June
AU - Kim, Kwang Mi
AU - Lee, Chang Hoon
AU - Shin, Jennifer H.
AU - Noh, Minsoo
PY - 2010/7
Y1 - 2010/7
N2 - 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) E2 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 PGE2-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.
AB - 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) E2 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 PGE2-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.
KW - Atopic dermatitis
KW - Cyclooxygenase-2
KW - Filaggrin
KW - NADPH oxidase 5
KW - Sphingosylphosphorylcholine
UR - http://www.scopus.com/inward/record.url?scp=77952289940&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2010.03.009
DO - 10.1016/j.bcp.2010.03.009
M3 - Article
C2 - 20230798
AN - SCOPUS:77952289940
SN - 0006-2952
VL - 80
SP - 95
EP - 103
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 1
ER -