Infliximab inhibits DNA repair in ultraviolet B‐irradiated premalignant keratinocytes

Abstract

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.

Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage

“…Nevertheless, the present exploratory trial included only a small sample size, limiting the statistical power. In conclusion, our data and results of previous studies indicate that combined treatment with broadband UVB and TNF‐α blockers might increase the risk of photocarcinogenesis 3–5,26,27 . The effect of TNF‐α blockers on the photocarcinogenic potential of narrowband UVB remains to be established 28,29 .…”

“…Faurschou et al. 26 recently observed that despite the fact that infliximab, a TNF‐α neutralizing antibody, blocks Akt and stimulates the G 2 /M checkpoint and apoptosis in UVB‐irradiated keratinocytes, the repair of cyclobutane pyrimidine dimers is impaired. They suggested that anti‐TNF‐α treatments may contribute to the accumulation of mutagenic lesions in the epidermis and enhance the early stages of skin carcinogenesis.…”

Effect of Infliximab on the UVB-Induced Apoptosis of Keratinocytes Infected by HPV38 E6/E7

“…In a previous ex vivo study, Gambichler et al [12] observed that etanercept, a recombinant human TNF- α receptor fusion protein, had no effect on the number of caspase-3 apoptotic cells present in skin biopsies of psoriasis patients treated with UVB and etanercept. In contrast, Faurschou et al [13] observed an unexpected increase of UVB-induced apoptosis in HaCaT keratinocytes exposed to infliximab despite enhanced G2/M cell cycle checkpoint and TNF- α -induced apoptosis. The authors suggested a reverse signalling pathway via membrane-bound TNF- α .…”

Synergism between narrowband ultraviolet B phototherapy and etanercept for the treatment of plaque-type psoriasis

“…Understandably, there is concern that anti‐TNF‐α treatments could be hazardous for the UV‐exposed skin by contributing to skin carcinogenesis through inducing mutagenic lesions in the epidermis and by reducing antitumour immunity . Indeed, ETN may affect the UVB‐induced apoptotic pathways.…”

“…In skin treated with erythemogenic doses [2 minimal erythemal doses (MEDs)] of UVB, immunoreactivity of cyclin D1 and p53 was significantly decreased at 24 h, and survivin expression was significantly higher if ETN was administered simultaneously . Furthermore, another anti‐TNF‐α inhibitor, the chimeric monoclonal antibody infliximab, was found to impair the repair of photoinduced cyclobutane pyrimidine dimer in the spontaneously immortalized, nontumorigenic human keratinocyte cell line HaCaT …”