Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition.
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.
Lind
Maria H
MH
Department of Bioscience, Clinical Research Center, Karolinska Institutet, Novum, SE-141 57 Huddinge, Sweden.
Rozell
Björn
B
Wallin
Robert P A
RP
van Hogerlinden
Max
M
Ljunggren
Hans-Gustaf
HG
Toftgård
Rune
R
Sur
Inderpreet
I
D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000503:physiopathology; D017931:DNA Primers; D004817:Epidermis / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
D017931:DNA Primers; D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha