title: Epidermal RelA specifically restricts contact allergen-induced inflammation and apoptosis in skin.
abstract: Strong inhibition of NF-κB signaling in the epidermis results in spontaneous skin inflammation in mice and men. As there is evidence for linkage between polymorphisms within the NF-κB signaling pathway and human inflammatory skin phenotypes, we asked whether partial functional inhibition of NF-κB signaling in epidermal keratinocytes can modulate clinically relevant skin inflammation. We therefore mutated rela specifically in the epidermis of mice (RelA(E-MUT) mice). These mice show no inflammatory phenotype. Induction of contact allergy, but not croton oil-induced irritant dermatitis, resulted in stronger ear swelling and increased epidermal thickness in RelA(E-MUT) mice. Both contact allergen and croton oil treatment led to increased expression of calgranulins A and B (S100A8/A9) in RelA(E-MUT) mice. Epidermal hyperproliferation in RelA(E-MUT) mice was non-cell autonomous as cultured primary epidermal keratinocytes from RelA(E-MUT) mice showed reduced proliferation compared with controls. These results demonstrate that epidermal RelA specifically regulates delayed-type hypersensitivity-induced skin inflammation. In addition, we describe here an essential but nonspecific function of RelA in the protection of epidermal keratinocytes from apoptosis. Our study identifies functions of NF-κB signaling in the epidermis and corroborates a specific role of epidermal keratinocytes in the regulation of skin inflammation.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany. Electronic address: skumari@uni-koeln.de.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Herzberg
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pofahl
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003436:Croton Oil / Q000009:adverse effects / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D009418:S100 Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000502:physiology*
chemical_list: D016328:NF-kappa B; C498144:Rela protein, mouse; D009418:S100 Proteins; D051996:Transcription Factor RelA; D003436:Croton Oil
references.citation: Nat Genet. 2009 Feb;41(2):199-204
references.pmid: 19169254
references.citation: J Virol. 2011 Sep;85(17):9013-22
references.pmid: 21715489
references.citation: J Biol Chem. 2001 Sep 21;276(38):35818-25
references.pmid: 11463791
references.citation: Mol Cell. 2000 Jun;5(6):981-92
references.pmid: 10911992
references.citation: Genes Dev. 1995 Nov 15;9(22):2723-35
references.pmid: 7590248
references.citation: J Biol Chem. 2001 Jan 12;276(2):1185-94
references.pmid: 11035014
references.citation: J Dermatol. 2010 Jun;37(6):512-21
references.pmid: 20536664
references.citation: J Cell Mol Med. 2010 Jun;14(6B):1760-76
references.pmid: 19538462
references.citation: Cell. 1995 Jan 27;80(2):331-40
references.pmid: 7834753
references.citation: Mol Cell Biol. 1996 May;16(5):2341-9
references.pmid: 8628301
references.citation: Am J Hum Genet. 2000 Dec;67(6):1555-62
references.pmid: 11047757
references.citation: Blood. 2001 Jan 1;97(1):46-55
references.pmid: 11133741
references.citation: Cell Death Differ. 2011 Jan;18(1):155-63
references.pmid: 20689557
references.citation: Eur J Immunol. 2000 Aug;30(8):2323-32
references.pmid: 10940923
references.citation: Br J Dermatol. 2006 Jul;155(1):62-6
references.pmid: 16792753
references.citation: Immunity. 2011 Mar 25;34(3):364-74
references.pmid: 21419662
references.citation: J Clin Invest. 2000 Jul;106(1):25-35
references.pmid: 10880045
references.citation: Am J Respir Cell Mol Biol. 2011 Sep;45(3):573-81
references.pmid: 21216972
references.citation: J Invest Dermatol. 2006 Mar;126(3):614-20
references.pmid: 16397523
references.citation: J Clin Invest. 2007 Jun;117(6):1490-501
references.pmid: 17525802
references.citation: Cell Death Differ. 2011 Dec;18(12):1845-53
references.pmid: 21566665
references.citation: Burns. 2010 Mar;36(2):152-63
references.pmid: 19766401
references.citation: Immunity. 2007 Aug;27(2):296-307
references.pmid: 17692539
references.citation: Biochem Biophys Res Commun. 2012 Jul 13;423(4):647-53
references.pmid: 22683330
references.citation: Nat Cell Biol. 2001 Feb;3(2):128-33
references.pmid: 11175744
references.citation: J Clin Invest. 2003 Oct;112(7):1108-15
references.pmid: 14523047
references.citation: J Cell Sci. 2007 Apr 15;120(Pt 8):1480-90
references.pmid: 17389689
references.citation: J Cell Biochem. 2008 May 15;104(2):453-64
references.pmid: 18044712
references.citation: Nature. 2000 May 25;405(6785):466-72
references.pmid: 10839543
references.citation: PLoS One. 2012;7(3):e33597
references.pmid: 22438958
references.citation: Am J Med Genet A. 2006 Jan 1;140(1):31-9
references.pmid: 16333836
references.citation: J Invest Dermatol. 2004 Jul;123(1):23-33
references.pmid: 15191538
references.citation: Genes Dev. 1995 Nov 15;9(22):2736-46
references.pmid: 7590249
references.citation: Photodermatol Photoimmunol Photomed. 1995 Aug;11(4):149-54
references.pmid: 8850247
references.citation: J Immunol. 1995 Sep 1;155(5):2459-67
references.pmid: 7544377
references.citation: Genes Dev. 2004 Jan 1;18(1):17-22
references.pmid: 14724177
references.citation: Cell Signal. 2003 Jan;15(1):1-7
references.pmid: 12401514
references.citation: Hum Mol Genet. 2006 Feb 15;15(4):531-42
references.pmid: 16399796
references.citation: Nature. 1995 Jul 13;376(6536):167-70
references.pmid: 7603567
references.citation: Int J Cancer. 2009 Aug 1;125(3):688-97
references.pmid: 19358264
references.citation: Nature. 2002 Jun 20;417(6891):861-6
references.pmid: 12075355
references.citation: J Invest Dermatol. 2004 Dec;123(6):1127-34
references.pmid: 15610524
references.citation: J Cell Sci. 2012 Feb 15;125(Pt 4):896-905
references.pmid: 22275433
references.citation: J Clin Invest. 2006 Aug;116(8):2094-104
references.pmid: 16886058
references.citation: J Exp Med. 2004 Sep 6;200(5):559-68
references.pmid: 15337789
references.citation: J Immunol. 2001 Aug 1;167(3):1592-600
references.pmid: 11466381
references.citation: J Invest Dermatol. 1996 Sep;107(3):377-83
references.pmid: 8751974
references.citation: J Clin Invest. 2000 Feb;105(3):253-60
references.pmid: 10675350
references.citation: Oncogene. 1999 Nov 22;18(49):6910-24
references.pmid: 10602466
references.citation: J Interferon Cytokine Res. 2002 Apr;22(4):407-12
references.pmid: 12034022
references.citation: J Biol Chem. 2006 Mar 10;281(10):6334-48
references.pmid: 16379012
references.citation: J Biol Chem. 1999 Dec 31;274(53):37957-64
references.pmid: 10608863
references.citation: Hepatology. 2009 Oct;50(4):1251-62
references.pmid: 19670424
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2307-12
references.pmid: 9482881
references.citation: J Invest Dermatol. 2003 Jan;120(1):48-55
references.pmid: 12535197
references.citation: Genesis. 2004 Apr;38(4):176-81
references.pmid: 15083518
references.citation: Curr Opin Investig Drugs. 2007 Jun;8(6):469-76
references.pmid: 17621877