Infliximab inhibits DNA repair in ultraviolet B-irradiated premalignant keratinocytes.
Anti-tumor necrosis factor-alpha (TNFalpha) approaches are increasingly used in the therapy of autoimmune diseases. One of the safety concerns is the potential enhancement of skin carcinogenesis. The aim of this study was to investigate if the TNFalpha neutralizing antibody, infliximab, directly affects the cell cycle and DNA repair in premalignant human keratinocytes after ultraviolet-B (UVB) irradiation. We found that infliximab-treated cells exhibited an enhanced G2/M cell cycle arrest and increased apoptosis after 10-20 mJ/cm(2) UVB. In spite of this, the level of cyclobutane pyrimidine dimers (CPD) in infliximab-treated cells was significantly increased at both 24 and 48 h after irradiation with 10 mJ/cm(2) UVB. As we have recently shown that protein kinase B/Akt is involved in the TNFalpha signalling pathway and promotes cell survival and skin carcinogenesis, we measured activatory phosphorylations of Akt (Ser-473 and Thr-308) and the signalling via related pathways Erk 1/2, p38 and p70-S6K. Infliximab inhibited Akt and its downstream targets p70-S6K and Erk 1/2, and stimulated p38 both in sham-irradiated and UVB-irradiated cells. In conclusion, despite the fact that infliximab blocks Akt and stimulates the G2/M checkpoint and apoptosis in UVB-irradiated keratinocytes, the repair of CPD is impaired. It is conceivable that anti-TNFalpha treatments may contribute to the accumulation of mutagenic lesions in the epidermis and enhance the early stages of skin carcinogenesis.
Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark. Af16@bbh.regionh.dk
Annesofie
A
Faurschou
Robert
R
Gniadecki
Hans Christian
HC
Wulf
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000069285:Infliximab; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D011740:Pyrimidine Dimers; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases