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Journal of Lipid Research, Vol. 49, 2571-2581, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Ceramide accelerates ultraviolet-induced MMP-1 expression through JAK1/STAT-1 pathway in cultured human dermal fibroblasts

Sangmin Kim¹, Yoonkyung Kim, Youngae Lee and Jin Ho Chung²

Department of Dermatology, Seoul National University College of Medicine, and Laboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National University Hospital, and Institute of Dermatological Science, Medical Research Center, Seoul National University, Seoul, Korea

Published, JLR Papers in Press, July 29, 2008.

This research was supported by a grant (R11-2002-097-06001-0) through the Center for Aging and Apoptosis Research at Seoul National University from the Korean Science & Engineering Foundation (KOSEF) and by a research agreement with the AmorePacific R&D Center.

¹ Present address of S. Kim: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710.

² To whom correspondence should be addressed. e-mail: jhchung{at}snu.ac.kr

Ultraviolet (UV) irradiation accelerates formation of ceramide through hydrolysis of sphingomyelin and de novo synthesis. Here, we investigated the effects of ceramide on UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Our results showed that acidic-sphingomyelinase (aSMase) and MMP-1 mRNA expression were increased by UV irradiation. Treatment of D609 (aSMase inhibitor) decreased the level of basal and UV-induced MMP-1 expression. On the other hand, basal and UV-induced MMP-1 expression was increased through induction of intracellular ceramide by D-MAPP, a ceramidase inhibitor. Our results also showed that MMP-1 protein expression was dose-dependently increased by C₂-ceramide or SMase treatment. The activation of ceramide pathway by C₂-ceramide enhanced phosphorylation of signal transducer and activators of transcription-1 (STAT-1), whereas ceramide-induced MMP-1 expression was potently prevented by piceatannol; Janus kinase (JAK1) inhibtor; and WHI-P131, a specific inhibitor of JAK3; but not by AG490, JAK 2 inhbitor, in human dermal fibroblasts. We also found that UV induced the phosphorylation of STAT-1, and UV-induced MMP-1 expression was significantly decreased by JAK1 inhibitor, piceatannol. Overall, we demonstrate that induction of intracellular ceramide by UV may activate MMP-1 gene expression via JAK1/STAT-1 pathway. Therefore, we suggest that targeted modulation of the ceramide signaling pathway may offer a novel therapeutic approach for inhibiting MMP-1 expression, which is a causing gene of skin aging.

Supplementary key words aSMase • UV • JAK3

Abbreviations: aSMase, acidic sphingomyelinase; ERK, extracellular signal-regulated kinase; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MOI, multiplicity of infection; MMP-1, matrix metalloproteinase-1; MTT, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxan; STAT-1, signal transducer and activators of transcription-1; UV, ultraviolet

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