Abstract
Psoriasis is an inflammatory skin disease in which activated immune cells and the proinflammatory cytokine TNF are well-known mediators of pathogenesis. The transcription factor NF-κB is a key regulator of TNF production and TNF-induced proinflammatory gene expression, and both the psoriatic transcriptome and genetic susceptibility further implicate NF-κB in psoriasis etiopathology. However, the role of NF-κB in psoriasis remains controversial. We analyzed the function of canonical NF-κB in the epidermis using CRE-mediated deletion of p65 and c-Rel in keratinocytes. In contrast to animals lacking p65 or c-Rel alone, mice lacking both subunits developed severe dermatitis after birth. Consistent with its partial histological similarity to human psoriasis, this condition could be prevented by anti-TNF treatment. Moreover, regulatory T cells in lesional skin played an important role in disease remission. Our results demonstrate that canonical NF-κB in keratinocytes is essential for the maintenance of skin immune homeostasis and is protective against spontaneous dermatitis.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Animals, Newborn
-
Antibodies, Blocking / immunology
-
Antibodies, Blocking / pharmacology
-
Cells, Cultured
-
Dermatitis / genetics
-
Dermatitis / immunology
-
Dermatitis / metabolism
-
Epidermis / immunology*
-
Epidermis / metabolism
-
Epidermis / pathology
-
Female
-
Flow Cytometry
-
Gene Expression / immunology
-
Homeostasis / drug effects
-
Homeostasis / genetics
-
Homeostasis / immunology*
-
Keratinocytes / immunology
-
Keratinocytes / metabolism
-
Male
-
Mice, Knockout
-
Mice, Transgenic
-
Proto-Oncogene Proteins c-rel / genetics
-
Proto-Oncogene Proteins c-rel / immunology*
-
Proto-Oncogene Proteins c-rel / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Skin / immunology*
-
Skin / metabolism
-
Skin / pathology
-
T-Lymphocytes, Regulatory / immunology
-
T-Lymphocytes, Regulatory / metabolism
-
Transcription Factor RelA / genetics
-
Transcription Factor RelA / immunology*
-
Transcription Factor RelA / metabolism
-
Tumor Necrosis Factor-alpha / genetics
-
Tumor Necrosis Factor-alpha / immunology
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Antibodies, Blocking
-
Proto-Oncogene Proteins c-rel
-
Transcription Factor RelA
-
Tumor Necrosis Factor-alpha