在研究巨噬細胞分化的過程通常都會使用給予PMA的THP-1作為細胞模型來進行探討，已知給予PMA後會藉由啟動PKC的訊息傳遞路徑來促進THP-1的分化，但是目前為止都沒有明確的指出這其中的機制為何。而近幾十年來有發現一個新的蛋白質－PKD，屬於PKC的亞型，PKD被報導會調控細胞的遷移、分化、增生、膜的運送及免疫反應，但是PKD是否參與THP-1的分化是目前未知的。在這個研究中將要探討在THP-1分化過程中PKD所扮演的角色。首先，我們先利用PKD的抑制劑CID755673來確認PKD對THP-1分化的影響，從顯微鏡觀察細胞型態發現，給予PMA之後細胞的貼附能力增加，但若先給予抑制劑再以PMA誘導分化，細胞的貼附能力便會減少，另外從流氏細胞儀分析的結果顯示，給予PMA時確實會增加細胞表面抗原CD11b及CD14，但是若先給予CID755673時則會減少細胞表面抗原的表現，同樣的，在吞噬作用及胞飲作用的實驗結果也看到一樣的現象，先給予CID755673的組別吞噬及胞飲作用的能力會減少。由於成熟的巨噬細胞會分泌超氧陰離子引起免疫及發炎反應，所以接著利用DHE螢光染色來觀察超氧陰離子的分布及型態變化，發現在給予PMA兩天後，會增加超氧陰離子的表現量且有聚集的現象，在抑制PKD的表現之後其螢光強度便會減弱，且聚集的情形也會減少。最後利用西方墨點法檢測PKD活化的時間點，結果顯示，在給予PMA五至十分鐘後PKD就已被活化，約在四小時後磷酸化的程度才開始慢慢回復至平常或減少，代表分化的蛋白質ERK也在5分鐘就被活化，顯示THP-1正在進行分化，而若先給予PKC抑制劑¬¬GF109203x，PKD 磷酸化的程度則會受到抑制。綜合以上結果顯示在PMA誘導THP-1的分化過程中，PKD可以藉由PKC的調控來增加細胞表面抗原的表現以及促進功能的提升。

THP-1 is often used as a model of macrophage differentiation that stimulated with PMA. PMA can promote THP-1 differentiation through activate protein kinase C (PKC) has been well defined, but so far it cannot clearly indicate which the mechanism. However, protein kinase D (PKD), a novel PKC subtype, is found in past decade. PKD has been reported that regulates cell migration, differentiation, proliferation, membrane trafficking and immunoreactions. Nevertheless whether PKD involves in THP-1 differentiation is still unknown. In this study, we investigate the role of PKD in THP-1 differentiation. At first, we wanted to verify whether CID755673, PKD selective inhibitor, could affect THP-1 differentiation. We found that cell adhesion increased in PMA treatment, but the adhesion would reduce in CID755673 treatment which treated before PMA. Moreover, it indicated that CID755673 decresed surface maker, CD11b and CD14, expression level, and it also decreased phagocytosis and pinocytosis. Then, we used dihydroethidium dye to detect superoxide. We found that PMA increased the amount of superoxide after 2 days and CID755673 reduced the superoxide formation. Finally, we wanted to know the expression course of PKD during THP-1 differentiation. Western blot data showed that the phosphorylation of PKD were increased in 5 to 10 minutes after PMA treatment, and returned to normal level after 4 hours. The phosphorylation of ERK was also induced in 5 minutes after PMA treatment. Phosphorylation sites of PKD were inhibited after treated GF109203X. These results represent that PKD enhances not only surface marker but also function promotion by PKC activation in PMA-induced THP-1 differentiation.

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