title: The c-Rel subunit of NF-κB regulates epidermal homeostasis and promotes skin fibrosis in mice.
abstract: The five subunits of transcription factor NF-κB have distinct biological functions. NF-κB signaling is important for skin homeostasis and aging, but the contribution of individual subunits to normal skin biology and disease is unclear. Immunohistochemical analysis of the p50 and c-Rel subunits within lesional psoriatic and systemic sclerosis skin revealed abnormal epidermal expression patterns, compared with healthy skin, but RelA distribution was unaltered. The skin of Nfkb1(-/-) and c-Rel(-/-) mice is structurally normal, but epidermal thickness and proliferation are significantly reduced, compared with wild-type mice. We show that the primary defect in both Nfkb1(-/-) and c-Rel(-/-) mice is within keratinocytes that display reduced proliferation both in vitro and in vivo. However, both genotypes can respond to proliferative stress, with 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation and closure rates of full-thickness skin wounds being equivalent to those of wild-type controls. In a model of bleomycin-induced skin fibrosis, Nfkb1(-/-) and c-Rel(-/-) mice displayed opposite phenotypes, with c-Rel(-/-) mice being protected and Nfkb1(-/-) developing more fibrosis than wild-type mice. Taken together, our data reveal a role for p50 and c-Rel in regulating epidermal proliferation and homeostasis and a profibrogenic role for c-Rel in the skin, and identify a link between epidermal c-Rel expression and systemic sclerosis. Modulating the actions of these subunits could be beneficial for treating hyperproliferative or fibrogenic diseases of the skin.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fullard
authors.forename: Anna
authors.initials: A
authors.lastname: Moles
authors.forename: Steven
authors.initials: S
authors.lastname: O'Reilly
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.forename: David
authors.initials: D
authors.lastname: Faini
authors.forename: Julie
authors.initials: J
authors.lastname: Diboll
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Reynolds
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
authors.forename: Julia
authors.initials: J
authors.lastname: Reichelt
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
mesh_terms: D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011565:Psoriasis / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D001761:Bleomycin; C073701:Nfkb1 protein, mouse; D013755:Tetradecanoylphorbol Acetate
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