PMID- 20520628 OWN - NLM STAT- MEDLINE DCOM- 20101008 LR - 20180801 IS - 1523-1747 (Electronic) IS - 0022-202X (Linking) VI - 130 IP - 10 DP - 2010 Oct TI - Hydrolytic pathway protects against ceramide-induced apoptosis in keratinocytes exposed to UVB. PG - 2472-80 LID - 10.1038/jid.2010.153 [doi] AB - 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. FAU - Uchida, Yoshikazu AU - Uchida Y AD - Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA. uchiday@derm.ucsf.edu FAU - Houben, Evi AU - Houben E FAU - Park, Kyungho AU - Park K FAU - Douangpanya, Sounthala AU - Douangpanya S FAU - Lee, Yong-Moon AU - Lee YM FAU - Wu, Bill X AU - Wu BX FAU - Hannun, Yusuf A AU - Hannun YA FAU - Radin, Norman S AU - Radin NS FAU - Elias, Peter M AU - Elias PM FAU - Holleran, Walter M AU - Holleran WM LA - eng GR - AI059311/AI/NIAID NIH HHS/United States GR - AR051077/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20100603 PL - United States TA - J Invest Dermatol JT - The Journal of investigative dermatology JID - 0426720 RN - 0 (Ceramides) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.- (sphingosine kinase) RN - EC 3.5.1.23 (Acid Ceramidase) RN - EC 3.5.1.23 (Neutral Ceramidase) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Acid Ceramidase/genetics/*metabolism MH - *Apoptosis/drug effects/physiology/radiation effects MH - Cells, Cultured MH - Ceramides/toxicity MH - Cytoprotection/drug effects MH - Gene Expression Regulation, Enzymologic/radiation effects MH - Humans MH - Hydrolysis MH - *Keratinocytes/cytology/drug effects/radiation effects MH - Neutral Ceramidase/genetics/*metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism MH - RNA, Messenger/metabolism MH - RNA, Small Interfering MH - Signal Transduction/drug effects/radiation effects MH - Sphingosine/metabolism MH - Ultraviolet Rays/*adverse effects EDAT- 2010/06/04 06:00 MHDA- 2010/10/12 06:00 CRDT- 2010/06/04 06:00 PHST- 2010/06/04 06:00 [entrez] PHST- 2010/06/04 06:00 [pubmed] PHST- 2010/10/12 06:00 [medline] AID - S0022-202X(15)34575-9 [pii] AID - 10.1038/jid.2010.153 [doi] PST - ppublish SO - J Invest Dermatol. 2010 Oct;130(10):2472-80. doi: 10.1038/jid.2010.153. Epub 2010 Jun 3.