Th1 cytokines accentuate but Th2 cytokines attenuate ceramide production in the stratum corneum of human epidermal equivalents: an implication for the disrupted barrier mechanism in atopic dermatitis

J Dermatol Sci. 2012 Oct;68(1):25-35. doi: 10.1016/j.jdermsci.2012.07.004. Epub 2012 Jul 20.

Abstract

Background: Although the mechanism(s) involved in the ceramide deficiency in the stratum corneum (SC) of atopic dermatitis (AD) skin is unknown, Th2 type cytokines have been reported to down-regulate ceramide levels in the epidermis. However, almost all research to date has focused on ceramide levels in the whole epidermis, not just in the SC layers alone, which are predominantly responsible for the skin barrier function.

Objective: We highlighted the effects of Th1/Th2 cytokines on ceramide levels in the SC.

Methods: We developed a modified system of human epidermal equivalents in which epidermis without a SC is cultured for 1 week to generate complete SC layers after which ceramides are extracted from the separated SC layers and are then quantified as per SC protein.

Results: The addition of Th2 cytokines (IL-4/IL-6) at a concentration of 10nM resulted in a marked decrease in SC ceramide levels. The reduced ceramide content in the SC was accompanied by the down-regulated expression of the genes encoding serine-palmitoyl transferase-2, acid sphingomyelinase and β-glucocerebrosidase in the epidermis. In contrast, the addition of Th1 cytokines (GM-CSF/IFN-γ/TNF-α) at concentrations of 2.5 or 10nM resulted in a slight increase in SC ceramide levels, which were accompanied by no change or an increase in the expression of those genes encoding sphingolipid metabolic enzymes in the epidermis.

Conclusion: These findings suggest that the Th2 type of inflammation evoked in AD skin is one of the essential factors involved in down-regulating the levels of ceramide in the SC.

MeSH terms

  • Cells, Cultured
  • Ceramides / metabolism*
  • Cytokines / metabolism*
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / metabolism*
  • Down-Regulation
  • Epidermis / immunology
  • Epidermis / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Glucosylceramidase / genetics
  • Glucosylceramidase / metabolism
  • Humans
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • Recombinant Proteins / metabolism
  • Serine C-Palmitoyltransferase / genetics
  • Serine C-Palmitoyltransferase / metabolism
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Th2 Cells / immunology
  • Th2 Cells / metabolism*
  • Time Factors

Substances

  • Ceramides
  • Cytokines
  • Recombinant Proteins
  • Serine C-Palmitoyltransferase
  • Sphingomyelin Phosphodiesterase
  • Glucosylceramidase