title: Photoinflammatory responses to UV-irradiated ketoprofen mediated by the induction of ROS generation, enhancement of cyclooxygenase-2 expression, and regulation of multiple signaling pathways.
abstract: Ketoprofen (KP) is photolabile and undergoes degradation when irradiated by sunlight, causing the development of various skin diseases. In this study, we found that UVB-irradiated KP can lead to inflammatory responses mediated by the induction of COX-2 and production of PGE(2). The ability of cells to repair UVB-induced cyclobutane pyrimidine dimers was impaired by UVB-irradiated KP, which consequently facilitated UVB-induced DNA damage to keratinocytes. The reactive oxygen species (ROS) generated by the photodegradation of KP facilitate UVB-induced inflammation and apoptosis in HaCaT cells. Elevation of the COX-2 levels was inhibited by an NADPH oxidase inhibitor and an NF-kappaB inhibitor but was largely enhanced after glutathione depletion by buthionine sulfoximine. Inhibition of ERK1/2, p38, and PI3K signaling attenuated the induction of COX-2, whereas inhibition of JNK signaling by SP600125 had very little effect. UVB-irradiated KP provoked an appreciable accumulation of pSer(15)-p53/COX-2 complexes, but this nuclear association of complexes was partially inhibited by PD98059. Silencing of COX-2 with siRNA was associated with reduced p53 phosphorylation and enhanced KP-photoinduced loss of mitochondrial membrane potential and cleavage of caspase 3 and PARP. This induction of apoptosis was prevented by N-acetylcysteine. In conclusion, this study highlights the particular inflammatory response to a photooxidative drug and suggests that KP-photoinduced inflammatory responses are predominantly attributable to induction of ROS generation and directly impair DNA repair.
authors.affiliation: Research & Development Department, Nipro Patch Co., Ltd., Saitama 344-0057, Japan. liu@nipro-patch.co.jp
authors.forename: Shicheng
authors.initials: S
authors.lastname: Liu
authors.forename: Hideo
authors.initials: H
authors.lastname: Mizu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamauchi
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007660:Ketoprofen / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects*; D010782:Photolysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D017382:Reactive Oxygen Species; D007660:Ketoprofen; D051546:Cyclooxygenase 2