Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF- B inhibition

Department of Bioscience, Clinical Research Center, Karolinska Institutet, Novum, SE-141 57 Huddinge, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2004; 101(14):4972-7. DOI: 10.1073/pnas.0307106101


NF-kappaB signaling plays an important role in skin development and epidermal growth control. Moreover, inhibition of NF-kappaB signaling in murine epidermal keratinocytes in vivo, by expression of a keratin 5 (K5)-directed superrepressor form of inhibitor of NF-kappaB (IkappaBalpha), results in an inflammatory response characterized by a massive dermal infiltration of neutrophils, epidermal hyperplasia, and a rapid development of aneuploid squamous cell carcinomas (SCC). We now show that by crossing K5-IkappaBalpha mice onto a tumor necrosis factor receptor 1(Tnfr1)-null background, both the inflammatory and the tumorigenic responses are blocked. The specificity of the block is illustrated by the fact that K5-IkappaBalpha mice lacking the IL-1 receptor type 1 (Il1r1) develop inflammation and squamous cell carcinomas. Reconstitution of lethally irradiated K5-IkappaBalpha/Tnfr1(-/-) mice with Tnfr1(+/-) bone-marrow does not induce the inflammatory or the tumorigenic phenotype, indicating a critical dependence on Tnfr1-mediated signaling in skin cells or nonimmune cells. Our results suggest a critical role of local Tnfr1-mediated signaling and associated inflammatory response cooperating with repressed keratinocyte NF-kappaB signaling in driving skin cancer development.

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    • "They consist of widespread scaly plaques, which upon histological analysis show acanthosis, hyperkeratosis, dilation of dermal blood vessels, and infiltration by a mixed inflammatory infiltrate with neutrophils forming aggregates in the upper epidermis (Pasparakis et al., 2002; van Hogerlinden et al., 1999). Genetic ablation of TNFR1 in the whole body prevents the development of inflammatory skin lesions in both the K14- Cre Ikk2 fl/fl and the K5-IkBaSR mice (Lind et al., 2004; Pasparakis et al., 2002), demonstrating that TNF regulates the pathogenesis of skin inflammation in these models similarly to psoriasis in humans. Skin inflammation in K14-Cre Ikk2 fl/fl mice occurs independently of ab T cells but requires the presence of macrophages in the dermis (Stratis et al., 2006). "
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    • "In contrast to the accepted view of NF-κB as supporting carcinogenesis, tumor proliferation and survival, a murine model in which NF-κB activity is constitutively inhibited through the expression of the IκBα super-repressor (K5IκBαSR) demonstrates spontaneous SCC development [6]. Interestingly the tumors in K5IκBαSR mice were TNFR1 dependent [31], whereas the relaPD/wt tnfrsf1a-/- mice continue to develop KAs although perhaps at lower numbers (Figure 5C). In the study by van Hogerlinden, the K5-promoter transgene drives expression of the IκBα super-repressor in basal layer keratinocytes, restricting NF-κB inhibition to those cells. "
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