Leptomycin B reduces matrix metalloproteinase-9 expression and suppresses cutaneous inflammation.
Matrix metalloproteinase-9 (MMP-9), a type of gelatinase, plays many roles in tissue metabolism, especially in inflammation, and many regulatory elements have been reported in the promoter region of its encoding gene. Leptomycin B, which regulates the nucleo-cytoplasmic trafficking of proteins, including transcription-factor-related ones, has the potential to exert important biological effects. The addition of leptomycin B to keratinocytes in culture had no effect on matrix metalloproteinase-2 (another gelatinase) but caused the selective down-regulation of MMP-9 during the stimulation of differentiation with high Ca(2+) or transforming growth factor-beta, as well as during the stimulation of inflammation by tumor necrosis factor-alpha or interleukin-1alpha. This down-regulation depended on multiple regulatory elements in the promoter of MMP-9 including KRE-M9 (which we have recently identified), and a classical 12-o-tetradecanoyl-phorbol-13-acetate-responsive element. The topical application of leptomycin B to murine skin also effectively suppressed inflammation, including MMP-9 expression, after ultraviolet B irradiation. These results suggest that the application of leptomycin B and/or its derivatives could be useful for treating many inflammatory conditions.
Kobayashi
Takashi
T
Department of Dermatology, Clinical Biology of Extracellular Matrix (F7), Chiba University School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba 260-8677, Japan. tkobayas@derma01.m.chiba-u.ac.jp
Shinkai
Hiroshi
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D003872:Dermatitis / Q000188:drug therapy* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects
D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9; C038753:leptomycin B