Hydrolytic pathway protects against ceramide-induced apoptosis in keratinocytes exposed to UVB

J Invest Dermatol. 2010 Oct;130(10):2472-80. doi: 10.1038/jid.2010.153. Epub 2010 Jun 3.


Although ceramides (Cers) are key constituents of the epidermal permeability barrier, they also function as apoptogenic signals for UVB irradiation-induced apoptosis in epidermal keratinocytes. As epidermis is continuously exposed to UV irradiation, we hypothesized that Cer hydrolysis protects keratinocytes from UVB-induced apoptosis by attenuating Cer levels. Both low-dose UVB (L-UVB) (< 35 mJ cm(-2)) and high-dose UVB (H-UVB) (> or = 45 mJ cm(-2)) irradiation inhibited DNA synthesis in cultured human keratinocytes, but apoptosis occurred only after H-UVB. Whereas Cer production increased after both L- and H-UVB, it normalized only in L-UVB-exposed keratinocytes, but remained elevated after H-UVB. Both acidic ceramidase (aCDase) and neutral ceramidase (nCDase) activities declined after L- and H-UVB, but returned to normal only in L-UVB cells, with decreased CDase activities or mRNA or protein levels being sustained in H-UVB cells. Inhibition of CDase using either a CDase inhibitor, N-oleoylethanolamine, or small interfering RNA (siRNA) (either to a- and/or n-CDase(s)) sensitized keratinocytes to L-UVB-induced apoptosis in parallel with further Cer accumulation. Blockade of sphingosine kinase 1 (SPHK1) (but not SPHK2) by siRNA also increased apoptosis in L-UVB keratinocytes, revealing that conversion of sphingosine to sphingosine-1-phosphate (S1P) further protects keratinocytes from UVB-induced cell death. Thus, Cer → sphingosine → S1Pmetabolic conversion protects against UVB-induced, Cer-mediated apoptosis in keratinocytes, but excessive UVB overwhelms this mechanism, thereby leading to keratinocyte apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Ceramidase / genetics
  • Acid Ceramidase / metabolism*
  • Apoptosis* / drug effects
  • Apoptosis* / physiology
  • Apoptosis* / radiation effects
  • Cells, Cultured
  • Ceramides / toxicity
  • Cytoprotection / drug effects
  • Gene Expression Regulation, Enzymologic / radiation effects
  • Humans
  • Hydrolysis
  • Keratinocytes* / cytology
  • Keratinocytes* / drug effects
  • Keratinocytes* / radiation effects
  • Neutral Ceramidase / genetics
  • Neutral Ceramidase / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Sphingosine / metabolism
  • Ultraviolet Rays / adverse effects*


  • Ceramides
  • RNA, Messenger
  • RNA, Small Interfering
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Acid Ceramidase
  • Neutral Ceramidase
  • Sphingosine