Localized inflammatory skin disease following inducible ablation of I kappa B kinase 2 in murine epidermis.
Skin inflammation is a complex process that involves interactions between various cell types residing in different skin compartments. Using mice with conditionally targeted I kappa B kinase 2 (IKK2) alleles, we have previously shown that epidermal keratinocytes can play a dominant role in the initiation of an inflammatory reaction. In order to investigate long-term consequences of IKK2 deletion in adult skin, we have generated mice with floxed IKK2 alleles in which expression of a Tamoxifen-inducible Cre recombinase construct is targeted to epidermal keratinocytes (K14-Cre-ER(T2)IKK2(fl/fl) mice). K14-Cre-ER(T2)IKK2(fl/fl) mice are born normally and do not show signs of a skin disease until the age of 6 months. Deletion of IKK2 can be observed after Tamoxifen application to the back skin or spontaneously, without Tamoxifen application, in mice older than 6 months. This deletion is accompanied by dramatic, localized skin changes that are characterized by invasion of inflammatory cells, hair follicle disruption, and pseudoepitheliomatous hyperplasia of the epidermis, but not by tumor formation. The hyperplastic epithelium shows increased phosphorylation of signal transducer and activator of transcription 3 and extracellular signal-regulated protein kinase 1/2, typical features of psoriatic epidermis. Our results identify a primary role for IKK2 in the development of skin inflammation and confirm its requirement for the maintenance of skin homeostasis.
Stratis
Athanasios
A
Department of Dermatology, University of Cologne and Center for Molecular Medicine, University of Cologne (CMMC), Cologne, Germany.
Pasparakis
Manolis
M
Markur
Doreen
D
Knaup
Renate
R
Pofahl
Ruth
R
Metzger
Daniel
D
Chambon
Pierre
P
Krieg
Thomas
T
Haase
Ingo
I
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003872:Dermatitis / Q000209:etiology* / Q000473:pathology; D017353:Gene Deletion; D018859:Hair Follicle / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics*; D019426:Integrases / Q000502:physiology; D053547:Keratin-14; D015603:Keratinocytes / Q000502:physiology; D007633:Keratins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000502:physiology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology
D053547:Keratin-14; C507446:Krt14 protein, mouse; D050796:STAT3 Transcription Factor; D013629:Tamoxifen; D007633:Keratins; D051550:I-kappa B Kinase; C045073:Cre recombinase; D019426:Integrases