title: Activation of cutaneous protein kinase C alpha induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways.
abstract: Skin keratinocytes are major mediators of host immune responses. The skin is also a target for immunologically based inflammation in many pathological states. Activation of protein kinase C (PKC) can induce cutaneous inflammation, but the precise role of each of six cutaneous PKC isoforms (alpha, delta, epsilon, eta, zeta, mu) that regulate normal skin homeostasis or contribute to skin pathology has not been clarified. We generated transgenic mice that overexpress PKCalpha in the basal layer of the epidermis and the outer root sheath of hair follicles under the regulation of the bovine keratin 5 promoter. K5-PKCalpha transgenic mice exhibit severe intraepidermal neutrophilic inflammation and disruption of the epidermis and upper hair follicles when treated topically with 12-O-tetradecanoylphorbol-13-acetate (TPA). Both TPA and UVB cause apoptosis in transgenic skin, but only TPA evokes intraepidermal inflammation. TPA also induces apoptosis in cultured transgenic keratinocytes, and this is prevented by an AP-1 dominant-negative construct. However, inhibiting AP-1 in vivo does not abrogate intraepidermal inflammation. Transcripts for specific cytokines and chemokines are elevated in TPA-treated cultured transgenic keratinocytes, and conditioned culture medium from these cells promotes neutrophil migration in vitro. Chemokine expression and neutrophil migration are not diminished by inhibiting AP-1. Thus, PKCalpha activation induces keratinocyte apoptosis via an AP-1-dependent pathway and mediates chemokine induction and intraepidermal inflammation independently. This model system will be useful to define specific chemokines regulated by PKCalpha that promote intraepidermal neutrophilic inflammation, a condition that characterizes several human cutaneous diseases such as pustular psoriasis and acute generalized exanthematous pustulosis.
authors.affiliation: Laboratories of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute/NIH, 37 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joseloff
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Murillas
authors.forename: Alice
authors.initials: A
authors.lastname: Wang
authors.forename: Coralyn
authors.initials: C
authors.lastname: Atwell
authors.forename: Sara
authors.initials: S
authors.lastname: Torgerson
authors.forename: Michael
authors.initials: M
authors.lastname: Gerdes
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Subleski
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Gao
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Charles
authors.initials: C
authors.lastname: Vinson
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D004817:Epidermis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015603:Keratinocytes / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051571:Protein Kinase C-alpha; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D019076:Transgenes
chemical_list: D018925:Chemokines; D016207:Cytokines; D018808:Transcription Factor AP-1; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha