UVA induces granzyme B in human keratinocytes through MIF: implication in extracellular matrix remodeling.
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.
Hernandez-Pigeon
Hélène
H
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.
Jean
Christine
C
Charruyer
Alexandra
A
Haure
Marie-José
MJ
Baudouin
Caroline
C
Charveron
Marie
M
Quillet-Mary
Anne
A
Laurent
Guy
G
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
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