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.
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.
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发表时间：
1999-10
影响因子：
4
通讯作者：
Hui Qin Wang;R. Smart
中科院分区：
文献类型：
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作者：
Hui Qin Wang;R. Smart
蛋白激酶Calpha（PKCalpha）是在小鼠表皮角质形成细胞中表达的六种PKC亚型之一。为了了解表皮PKCalpha的作用，我们将其表达定位于正常小鼠皮肤的特定细胞，并检查了角蛋白5（K5）启动子指导的PKCalpha在转基因小鼠中表达的效果。在正常小鼠皮肤中，PKCalpha在生长期毛囊的外根鞘（ORS）角质形成细胞中广泛表达，在毛囊间表皮的角质形成细胞中弱表达。K5靶向表达PKCalpha表皮基底角质形成细胞和滤泡ORS角质形成细胞导致表皮PKCalpha增加10倍。K5-PKCalpha小鼠在表皮中的角质形成细胞生长和分化中未表现出异常。然而，用PKC激活剂12-O-十四酰基佛波醇-13-乙酸酯（TPA）进行的单一局部治疗导致显著的炎症反应，其特征在于水肿和中性粒细胞的广泛表皮浸润，其在表皮中形成表皮内微隆起。与TPA处理的野生型小鼠相比，TPA处理的K5-PKCalpha小鼠的表皮表现出环氧合酶-2（考克斯-2）、中性粒细胞趋化因子巨噬细胞炎性蛋白-2（MIP-2）mRNA和促炎细胞因子TNF α mRNA的表达增加，但IL-6或IL-1 α mRNA的表达没有增加。为了确定K5-PKCalpha小鼠是否显示对TPA促进的改变的应答，用TPA促进7，12-二甲基苯并[a]蒽启动的K5-PKCalpha小鼠和野生型小鼠。在K5-PKCalpha小鼠和野生型同窝小鼠之间未观察到乳头状瘤发病率或多样性的差异。这些结果表明，表皮中PKCalpha的过表达增加了特异性促炎介质的表达并诱导皮肤炎症，但对表皮分化、增殖或TPA肿瘤促进几乎没有影响。
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.