Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion.
Protein kinase Calpha (PKCalpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of epidermal PKCalpha, we have localized its expression to specific cells of normal mouse skin and examined the effect of keratin 5 (K5) promoter directed expression of PKCalpha in transgenic mice. In normal mouse skin, PKCalpha was extensively expressed in the outer root sheath (ORS) keratinocytes of the anagen hair follicle and weakly expressed in keratinocytes of interfollicular epidermis. K5-targeted expression of PKCalpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increase in epidermal PKCalpha. K5-PKCalpha mice exhibited no abnormalities in keratinocyte growth and differentiation in the epidermis. However, a single topical treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a striking inflammatory response characterized by edema and extensive epidermal infiltration of neutrophils that formed intraepidermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKCalpha mice displayed increased expression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor macrophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokine TNFalpha mRNA but not IL-6 or IL-1alpha mRNA. To determine if K5-PKCalpha mice display an altered response to TPA-promotion, 7, 12-dimethylbenz[a]anthracene-initiated K5-PKCalpha mice and wild-type mice were promoted with TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKCalpha mice and wild-type littermates. These results demonstrate that the overexpression of PKCalpha in epidermis increases the expression of specific proinflammatory mediators and induces cutaneous inflammation but has little to no effect on epidermal differentiation, proliferation or TPA tumor promotion.
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Molecular and Cellular Toxicology, Department of Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA. rcsmart@unity.ncsu.edu
Smart
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RC
D000038:Abscess / Q000139:chemically induced; D000818:Animals; D002417:Cattle; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000235:genetics; D051546:Cyclooxygenase 2; D004487:Edema / Q000139:chemically induced; D004789:Enzyme Activation; D004817:Epidermis / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D006197:Hair / Q000201:enzymology; D007249:Inflammation; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology; D007633:Keratins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015846:Monokines / Q000235:genetics*; D009504:Neutrophils / Q000502:physiology; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D007527:Isoenzymes; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007633:Keratins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate