鋰鹽誘導 C6 神經膠瘤細胞血紅素氧化酵素 -1 之表現
鋰鹽（ Lithium chloride ， LiCl ）長期用來治療躁鬱症的雙極性情感疾病（ bipolar disor der ）。但其作用機制尚未完全釐清。
由於血紅素氧化酵素 -1 （ heme oxygenase-1 ， HO-1 ）具有抗發炎、抗氧化抗細胞凋 亡及免疫調節等功能。本研究利用 C6 神經膠瘤細胞（ C6 glioma cells ）探討 lithium 是 否可以誘導 HO-1 的表現。我們發現鋰鹽的確可以造成 HO-1 蛋白劑量及時間依存性的 誘導作用。加入自由基的淨化劑 l-N-acetylcysteine （ l-NAC ）、 phosphatidylinositol 3- kinase （ PI3-K ）及 p38 抑制劑會抑制 lithium 誘導 HO-1 的表現。 Lithium 會藉由活化 reactive oxygen species （ ROS ）經 PI3-K 及 p38 pathway 表現 HO-1 ，但不藉由 extracel lular responsive kinase （ ERK44/42 ）及 c-Jun NH2-terminal kinase /stress-activated protei n Kinase （ JNK ）訊息傳遞路徑。近年來研究指出， NF-E2 related factor 2 （ Nrf-2 ） 可經 PI3-K 與 MAPK 訊息傳遞路徑調控 HO-1 基因的表現。我們發現 lithium 可以增加 累積細胞核 Nrf-2 蛋白。當加入 lithium 前處理後，以革蘭氏陰性菌細胞壁成份（ lipopo lysaccharide ， LPS ）刺激 C6 神經膠瘤細胞，由於可以大幅抑制 LPS 所誘導型一氧化 氮合成（ inducible NOS ， iNOS ）表現，利用 tin protophyrin dichlorideⅨ （ SnPP ， H O-1 抑制劑）可阻斷鋰鹽抑制 nitrite 產生的抑制作用。由於使用 tricarbonyl dichlororuthe nium （ II ）（ CO donor ）可以抑制 iNOS 的表現，而以血紅素清除 CO 又可阻斷鋰鹽 對 nitrite 產生的抑制作用，進一步顯示鋰鹽可以誘導 HO-1 並藉由血鐵素的降解而產生 CO ，而抑制在 C6 神經膠瘤細胞 LPS 刺激的 iNOS 表現。
本篇研究論文證明在 C6 神經膠瘤細胞中， lithium 誘導 HO-1 表現是透過 ROS 活化 PI 3-K 與 MAPK 訊息傳遞路徑，使細胞核內 Nrf-2 累積進一步持續表現 HO-1 ，而 lithium 抗發炎反應是透過產生 HO-1/CO 的訊息傳遞。Lithium Induces Heme Oxygenase-1 Expression in C6 Glioma Cells
Lithium has been used to treat bipolar disorder. However, the underneath mechanisms are not completely e lucidated.
In the present study, we investigated whether lithium influences the heme oxygenase-1 (HO-1) protein leve l in C6 glioma cells. Lithium induced dose- and time- dependent manner increases of HO-1 expression in C 6 glioma cells. l-N-acetylcysteine, a free radical scavenger, inhibited lithium-induced HO-1 expression in C6 glioma cells, suggesting reactive oxygen species (ROS) may be involved in the induction of HO-1 expr ession. Treatment of cells with PI 3-Kinase specific inhibitor, LY294002 or the p38 MAPK specific inhibit or, SB203580, blocked lithium induced HO-1 expression. However, the specific p42/44 MAPK inhibitor, P D98059 or the specific JNK inhibitor, SP600125, had no effect on lithium induced HO-1 expression. In the present studies, Nrf-2 can regulate HO-1 expression goes through PI3K and MAPK pathway. We find that lithium induced the nuclear accumulation of Nrf-2. Given HO-1 expression has been linked to anti-inflam matory effect, we investigated whether treatment of C6 glioma cells with lithium inhibited LPS-inducible n itric oxide syntheses (iNOS) and nitric oxide (NO) expression. Lithium can inhibit LPS-induced iNOS and NO expression. Pretreatment with tricarbonyl dichorouthenium II (CO donor), inhibited LPS-induced iNO S and NO expression, suggesting CO mediated the inhibitory effect by lithium, and scavenging CO with he moglobin suppressed lithium inhibition in LPS-induced iNOS expression.
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