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 C alpha (PKC alpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of e pidermal PKC alpha, we have localized its expression to specific cells of n ormal mouse skin and examined the effect of keratin 5 (K5) promoter directe d expression of PKC alpha in transgenic mice. In normal mouse skin, PKC alp ha was extensively expressed in the outer root sheath (ORS) keratinocytes o f the anagen hair follicle and weakly expressed in keratinocytes of interfo llicular epidermis. K5-targeted expression of PKC alpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increa se in epidermal PKC alpha. K5-PKC alpha 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-ace tate (TPA) resulted in a striking inflammatory response characterized by ed ema and extensive epidermal infiltration of neutrophils that formed intraep idermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKC alpha mice displayed increased ex pression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor mac rophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokin e TNF alpha mRNA but not IL-6 or IL-1 alpha mRNA. To determine if K5-PKC al pha mice display an altered response to TPA-promotion, 7,12-dimethylbenz[a] anthracene-initiated K5-PKC alpha mice and wild-type mice were promoted wit h TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKC alpha mice and wild-type littermates. These results demonstr ate that the overexpression of PKC alpha in epidermis increases the express ion of specific proinflammatory mediators and induces cutaneous inflammatio n but has little to no effect on epidermal differentiation, proliferation o r TPA tumor promotion.