Photoinflammatory responses to UV-irradiated ketoprofen mediated by the induction of ROS generation, enhancement of cyclooxygenase-2 expression, and regulation of multiple signaling pathways.
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.
Liu
Shicheng
S
Research & Development Department, Nipro Patch Co., Ltd., Saitama 344-0057, Japan. liu@nipro-patch.co.jp
Mizu
Hideo
H
Yamauchi
Hitoshi
H
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
D017382:Reactive Oxygen Species; D007660:Ketoprofen; D051546:Cyclooxygenase 2