title: Human keratinocytes acquire cellular cytotoxicity under UV-B irradiation. Implication of granzyme B and perforin.
abstract: Ultraviolet (UV) radiation from the sun is widely considered as a major cause of human skin photoaging and skin cancer. Granzyme B (GrB) and perforin (PFN) are two proteins contained in granules and implicated in one of the mechanisms by which cytotoxic lymphocytes and natural killer cells exert their cytotoxicity against virus-infected, alloreactive, or transformed cells. The distribution of GrB and PFN in the skin has received little attention. However, Berthou and co-workers (Berthou, C., Michel, L., Soulie, A., Jean-Louis, F., Flageul, B., Dubertret, L., Sigaux, F., Zhang, Y., and Sasportes, M. (1997) J. Immunol. 159, 5293-5300) described that, whereas freshly isolated epidermal cells did not express GrB or PFN, keratinocyte growth to confluence was associated with GrB and PFN mRNA and protein synthesis. In this work, we have investigated the possible role of UV-B on GrB and PFN expression in keratinocytes. We found that UV-B induces GrB and PFN expression in these cells through redox-, epidermal growth factor receptor-, and mitogen-activated protein kinase-dependent signaling. Furthermore, under UV irradiation, keratinocytes acquire a significant cytotoxicity, which is GrB and PFN dependent, toward a variety of cellular targets including transformed T-lymphocytes, melanocytes, and keratinocytes. This phenomenon may have important functional consequences in the regulation of skin inflammatory response and in the emergence of cancer skin.
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France. Electronic address: helene.hernandez@toulouse.inserm.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Hernandez-Pigeon
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Charruyer
authors.affiliation: CERPER, Institut de Recherche Pierre Fabre, Laboratoire de Biologie Cellulaire Cutanée, Toulouse, France.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Haure
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Titeux
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Tonasso
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Quillet-Mary
authors.affiliation: CERPER, Institut de Recherche Pierre Fabre, Laboratoire de Biologie Cellulaire Cutanée, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Baudouin
authors.affiliation: CERPER, Institut de Recherche Pierre Fabre, Laboratoire de Biologie Cellulaire Cutanée, Toulouse, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Charveron
authors.affiliation: INSERM U563, CPTP, Bat B, Pavillon Lefebvre, Place du Dr. Baylac, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse cedex 3, France; Service d'Hématologie, Centre Hospitalier Universitaire Purpan, 31059 Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
mesh_terms: D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects; D053804:Granzymes; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008544:Melanocytes; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes; D014466:Ultraviolet Rays
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; D066246:ErbB Receptors; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases