title: UVA induces granzyme B in human keratinocytes through MIF: implication in extracellular matrix remodeling.
abstract: In a previous study, we have described that UVB induces granzyme B (GrB) in human keratinocyte cells, and that confers potent cellular cytotoxicity against various cellular models, including immune cells (Hernandez-Pigeon, H., Jean, C., Charruyer, A., Haure, M. J., Titeux, M., Tonasso, L., Quillet-Mary, A., Baudouin, C., Charveron, M., and Laurent, G. (2006) J. Biol. Chem. 281, 13525-13532). Herein, we have found that, in contrast to UVB, UVA failed to enhance keratinocyte cellular cytotoxicity but was still able to trigger GrB production. We show that GrB is accumulated through a p38 MAPK-dependent transcriptional mechanism stimulated by redox-dependent migration inhibitory factor release. Moreover, GrB purified from UVA-treated cellular extracts was found to degrade fibronectin in vitro. Treatment with antisense oligonucleotide directed against GrB resulted in the inhibition of UVA-induced cell detachment and cell death and facilitated cell migration through fibronectin and vitronectin matrix upon UVA exposure. Altogether, these results suggest another function for GrB in the context of the UV response. Indeed, combined with our previous study, it appears that, whereas this enzyme mediates keratinocyte cellular cytotoxicity following UVB irradiation, GrB supports the capacity of keratinocyte to degrade extracellular matrix components following UVA irradiation. UV-mediated GrB production may thus have important consequences in photoaging and photocarcinogenesis.
authors.affiliation: INSERM U563, CPTP (Centre de Physiopathologie Toulouse Purpan) Bat. B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Hernandez-Pigeon
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.forename: Alexandra
authors.initials: A
authors.lastname: Charruyer
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Haure
authors.forename: Caroline
authors.initials: C
authors.lastname: Baudouin
authors.forename: Marie
authors.initials: M
authors.lastname: Charveron
authors.forename: Anne
authors.initials: A
authors.lastname: Quillet-Mary
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
mesh_terms: D002465:Cell Movement; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000528:radiation effects; D005353:Fibronectins / Q000378:metabolism; D053804:Granzymes / Q000096:biosynthesis*; D006801:Humans; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005353:Fibronectins; D008263:Macrophage Migration-Inhibitory Factors; D016376:Oligonucleotides, Antisense; D048051:p38 Mitogen-Activated Protein Kinases; D053804:Granzymes; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human