Wheeler Deric L, Reddig Peter J, Ness Kristin J, Leith Catherine P, Oberley Terry D, Verma Ajit K
Department of Human Oncology, Medical School, University of Wisconsin, K4/532 CSC Clinical Science Center, 600 Highland Ave., Madison, WI 53792, USA.
Am J Pathol. 2005 Jan;166(1):117-26. doi: 10.1016/s0002-9440(10)62237-7.
Protein kinase C (PKC)-epsilon, a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the PKC isoforms expressed in mouse epidermis. We reported that FVB/N transgenic mouse lines that overexpress (8- or 18-fold) PKC-epsilon protein in basal epidermal cells and cells of the hair follicle develop papilloma-independent squamous cell carcinoma (SCC) elicited by 7,12-dimethylbenz(a)anthracene initiation and 12-O-tetradecanoylphorbol-13-acetate-promotion or by repeated ultraviolet radiation exposures. The susceptibility to the development of SCC was proportional to the level of expression of the PKC-epsilon transgene. We now report that PKC-epsilon FVB/N transgenic mice (line 215) that overexpress in epidermis approximately 18-fold PKC-epsilon protein more than their wild-type littermates spontaneously develop a myeloproliferative-like disease (MPD) in 100% of PKC-epsilon transgenic mice. The MPD was characterized by an excess of neutrophils and eosinophils, resulting in invasion of almost all vital organs of the mouse by 6 months of age. On gross examination these mice present with splenomegaly, hepatomegaly, and severe lymphadenopathy. Examination of the bone marrow revealed almost complete effacement by neutrophils, eosinophils, and their precursors. Furthermore, the spleen and lymph nodes were enlarged and exhibited marked extramedullary hematopoiesis. Complete pathological analysis of the second PKC-epsilon transgenic mouse (line 224) that expresses approximately eightfold PKC-epsilon protein more than their wild-type littermates revealed no remarkable findings in any of the affected organs as seen in line 215. However, peripheral blood analyses of PKC-epsilon transgenic mice indicated significant increases of neutrophils in the circulating blood in both PKC-epsilon transgenic lines. To determine whether there was an imbalance of cytokines in PKC-epsilon transgenic mice (line 215), resulting in aberrant myelopoiesis, we analyzed 17 cytokines in the peripheral blood. This analysis indicated that interleukin-5, interleukin-6, and granulocyte-colony stimulating factor were up-regulated as a function of age. The transgene PKC-epsilon was not detected in any of the affected organs (bone marrow, liver, spleen, lung) We suggest that overexpression of PKC-epsilon in the epidermis may lead to the induction of specific cytokines that may, in a paracrine mechanism, perturb normal hematopoiesis in bone marrow resulting in a granulocytic skew toward that of neutrophils and eosinophils. The susceptibility of PKC-epsilon transgenic mice to the induction of SCC and the spontaneous development of MPD are unrelated.
蛋白激酶C（PKC）-ε是一种不依赖Ca²⁺、依赖磷脂的丝氨酸/苏氨酸激酶，是在小鼠表皮中表达的PKC亚型之一。我们报道，在基底表皮细胞和毛囊细胞中过表达（8倍或18倍）PKC-ε蛋白的FVB/N转基因小鼠品系，在7,12-二甲基苯并(a)蒽启动和12-O-十四酰佛波醇-13-乙酸酯促进下，或在反复紫外线照射后，会发生不依赖乳头瘤的鳞状细胞癌（SCC）。对SCC发生的易感性与PKC-ε转基因的表达水平成正比。我们现在报道，在表皮中比其野生型同窝小鼠过表达约18倍PKC-ε蛋白的PKC-ε FVB/N转基因小鼠（215系），100%的PKC-ε转基因小鼠会自发发生骨髓增殖样疾病（MPD）。MPD的特征是中性粒细胞和嗜酸性粒细胞过多，到6月龄时几乎导致小鼠所有重要器官被侵袭。大体检查这些小鼠出现脾肿大、肝肿大和严重的淋巴结病。骨髓检查显示几乎完全被中性粒细胞、嗜酸性粒细胞及其前体细胞取代。此外，脾脏和淋巴结肿大并表现出明显的髓外造血。对第二个PKC-ε转基因小鼠（224系）进行的完整病理分析显示，其比野生型同窝小鼠多表达约8倍的PKC-ε蛋白，在任何受影响的器官中均未发现如215系所见的显著异常。然而，对PKC-ε转基因小鼠的外周血分析表明，两个PKC-ε转基因系的循环血液中中性粒细胞均显著增加。为了确定PKC-ε转基因小鼠（215系）中是否存在细胞因子失衡，导致异常的骨髓生成，我们分析了外周血中的17种细胞因子。该分析表明，白细胞介素-5、白细胞介素-6和粒细胞集落刺激因子随年龄上调。在任何受影响的器官（骨髓、肝脏、脾脏、肺）中均未检测到转基因PKC-ε。我们认为，表皮中PKC-ε的过表达可能导致特定细胞因子的诱导，这些细胞因子可能通过旁分泌机制扰乱骨髓中的正常造血，导致粒细胞向中性粒细胞和嗜酸性粒细胞倾斜。PKC-ε转基因小鼠对SCC诱导和MPD自发发生的易感性无关。
