title: Sphingosylphosphorylcholine is a potent inducer of intercellular adhesion molecule-1 expression in human keratinocytes.
abstract: We recently reported that the epidermis of patients with atopic dermatitis contains an abnormally expressed sphingomyelin deacylase that yields a large amount of sphingosylphosphorylcholine (SPC) rather than ceramide. In this study, we characterize inflammatory roles of newly discovered chemicals in the epidermis by elucidating biologic effects of SPC on intercellular adhesion molecules-1 (ICAM-I) expression by human keratinocytes in culture in comparison with other sphingolipids. Using fluorescence-activated cell sorter analysis, we found that SPC treatment at concentrations of 10-20 microM significantly enhanced the expression of ICAM-I by cultured human keratinocytes in a dose-dependent manner after incubation for 15-24 h, and, using northern blot analysis, that this was accompanied by increased expression of ICAM-1 mRNA within 4 h of incubation. Transforming necrosis factor-alpha (TNF-alpha) levels in the medium of keratinocytes treated at a 10 microM concentration of SPC were significantly increased by 200%. Furthermore, the SPC-induced ICAM-1 expression was partially abolished by the concomitant addition of anti-TNF-alpha, suggesting a partial autocrine involvement of TNF-alpha in ICAM-1 expression. Assay of mitogen-activated protein kinase revealed that 10 microM SPC induced a rapid activation of mitogen-activated protein kinase in human keratinocytes, including an increase in its phosphorylation within 5 min, which then declined to the baseline control level after 30 min. In contrast, sphingomyelin or sphingosine had no significant potential to activate mitogen-activated protein kinase at the same concentration. These findings suggest that SPC plays an important role in the inflammatory process of epidermis in skin diseases, such as atopic dermatitis, with high expression of sphingomyelin deacylase.
authors.affiliation: Biological Science Laboratories, Kao Corporation, Haga, Tochigi, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Imokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Higuchi
authors.forename: H
authors.initials: H
authors.lastname: Kondo
authors.forename: Y
authors.initials: Y
authors.lastname: Yada
mesh_terms: D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D015603:Keratinocytes / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D018799:Intercellular Adhesion Molecule-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013110:Sphingosine; D002118:Calcium