- 學位論文
鋰鹽對週邊血液單核球細胞衍生之樹突狀細胞的調控作用
Modulation of lithium chloride on the functions of peripheral blood mononuclear cell-derived dendritic cell
摘要
雙極性情感性躁鬱症是一個非常普遍的精神疾病，在美國大約有1.3-1.5％的人口罹患。它的症狀包含憂鬱和躁症兩個時期。鋰鹽和valproic acid為治療雙極性情感性躁鬱症的首選藥物，但他們的作用機轉並不清楚。在神經系統上，鋰鹽可以保護神經系統及防止凋亡；在免疫系統上，雙極性情感性躁鬱症服用情緒穩定藥的病人，被檢測出較容易罹患自體免疫病人，而服用鋰鹽治療的病患罹患的機率比較小。因此，我們有興趣研究鋰鹽在免疫系統之鑰—樹突狀細胞分子及功能上所扮演的角色。自人類周邊血液分離出單核球，將之培養七天成未成熟樹突狀細胞，並在培養第一天便給予不同濃度的鋰鹽。實驗發現給予鋰鹽2.5-10 mM可有意義的增加樹突狀細胞CD86和CD83的表現約2-3倍。但對其他樹突狀細胞表面記號如HLA-DR, CD80, CD40和CD14並無影響。鋰鹽刺激的未成熟樹突狀細胞與控制組比起來有意義的增加IL-6, IL-8, IL1-β和TNF-α的分泌約6-30倍。接下來我們研究經由鋰鹽刺激過的樹突狀細胞它刺激異體淋巴球的影響，發現鋰鹽對於異體淋巴球的增生並沒有影響。在T細胞的分化階段，我們測量細胞激素發現鋰鹽對於T細胞的分化與控制組沒有太大的不同。更進一步地，我們研究了它的訊號傳遞機制，給予Glycogen Synthase Kinase -3β (GSK-3β)抑制劑 (SB415286, SB216763, GSK-3β inhibitor I 和GSK-3β inhibitor VII)及mitogen- activated protein kinase kinase (MEK)抑制劑(PD98059)後發現樹突狀細胞表面記號並沒有顯著差異。反之，在給予phosphatidylinositol-3-kinase (PI3K)抑制劑LY294002後發現樹突狀細胞表面記號CD83和CD86有意義顯著降低。這些實驗數據顯示鋰鹽在調控樹突狀細胞的功能和免疫調節中可能扮演重要的角色。
並列摘要
Bipolar disorder is a common psychiatric disease in the world, its symptoms include alternating depressive and manic episodes. It affects 1.3-1.5％ of population in the U.S. lithium (Li) and valproic acid have been chosen as the first line medicine for bipolar disorder. However, their mechanisms remain unclear. Lithium could protect and prevent apoptosis of neuron cells. Patients with bipolar disorder have higher prevalence of autoimmune disease, but patients treated with LiCl have lower incidence. Therefore, we are interested in the effect of lithium on the functions of dendritic cells (DC), which is a key regulator of immune responses. Peripheral blood mononuclear cell (PBMC) derived DCs were generated and treated with lithium for examination of change of surface molecules, mixed lymphocyte reaction and cytokine production. We found that lithium could significantly increase the expression of CD86 and CD83 expression on DCs to 2-3 folds as compared to control. Furthermore, IL-8, IL-6, IL-1β and TNF-α secretion were increased by lithium approximately 6-30 folds. We found that lithium had no effect on allogeneic T lymphocytes proliferation in a mixed lymphocyte reaction. To assay of culture supernatant for T cell polarization, we found that no apparent secretion of Th1 or Th2 cytokines was observed. DC Treated with GSK-3β inhibitors (SB415286, SB216763, GSK-3β inhibitor I and GSK-3β inhibitor VII) and mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059) did not alter the profiling of surface markers expression in DCs. In contrast, phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 significantly decreased the expression of CD86 and CD83 in DCs. These data suggest that lithium could modulate DC functions, and might have potential role in immunomodulation.