臺灣博碩士論文加值系統

在過去二十年，敗血性休克經由革蘭氏陽性菌所引起的有增加的情形；的確，在所有的敗血症中有二分之一至三分之一是由革蘭氏陽性菌所造成的。研究指出一種源自金黃色葡萄球菌的革蘭氏陽性菌細胞壁產物如壁脂酸，會誘導腦脊髓炎及腦膜炎發生。壁脂酸也可以活化巨噬細胞引發一氧化氮酵素表現及增加一氧化氮的產生，然而壁脂酸是否可活化腦中小神經膠細胞目前並不清楚！
本實驗中，利用壁脂酸刺激初級培養中小神經膠細胞，發現會造成小神經膠細胞形態明顯的改變，且高濃度的壁脂酸會造成該細胞的死亡，然而低濃度的壁脂酸也會使小神經膠細胞有增殖的現象。壁脂酸刺激初級培養中小神經膠細胞也會增加其表面抗原如主要組織相容第二型抗原及細菌毒素其受體如補體第三型、CD14及清道夫受體的表現。另外，壁脂酸處理初級培養中小神經膠細胞會引發一氧化氮酵素的表現進而產生一氧化氮；而顯著的一氧化氮累積是在壁脂酸處理初級培養中小神經膠細胞二小時後便產生了。如果同時處以補體第三型、CD14或清道夫受體的抗體對一氧化氮的產生有顯著的抑制作用。壁脂酸刺激初級培養中小神經膠細胞也會使ERK、p38及JNK磷酸化。一氧化氮的產生也可以被p38或NFκB抑制劑所抑制，這顯示壁脂酸刺激初級培養中小神經膠細胞產生一氧化氮跟p38及NFκB有關。綜合這些結果證實革蘭氏陽性菌單一產物如壁脂酸可活化初級培養中小神經膠細胞產生一氧化氮，這過程是經由壁脂酸受體(如補體第三型、CD14或清道夫受體)，p38及NFκB這些訊息傳遞路徑所完成的。

The incidence of septic shock caused by gram-positive bacteria has been increasing over the past two decades. Currently, between one-third and one-half of all cases of sepsis are caused by gram-positive microorganisms. Lipoteichoic acid (LTA), a cell wall component from gram-positive bacterium (Staphylococcus aureus), could also induce encephalomyelitis and meningeal inflammation. LTA enhanced the production of nitric oxide (NO) through expression of iNOS in murine macrophages. Whether microglia can also be activated by the sole cell wall product of gram-positive bacteria, LTA, is unclear！
In the present study, we found that LTA significantly changed external morphology of isolated microglia and caused cell death at high concentration. LTA of low doses also enhanced microglial proliferation. MHC class II antigens and the potential receptors for LTA such as the complement type 3 (CR3), CD14 and macrophage scavenger receptors (SR) on microglia were also augmented after LTA treatment. The latter further induced NO release and inducible nitric oxide synthase (iNOS) expression. LTA-induced NO accumulation was detected as early as at 2 h in microglial culture and significantly attenuated by the pretreatment with anti-CD14, CR3 or SR antibody. LTA activated phosphorylated p38, ERK or JNK in cultured microglia. NO production also drastically decreased by SB203580 (p38 inhibitor) or pyrrolidine dithiocarbanate (an inhibitor of nuclear factor κB), indicating that p38 and NFκB were involved in microglial NO release after LTA challenge. These results suggest that gram-positive bacterial product such as LTA can activate microglia to release NO via the signal transduction pathway involving in LTA receptors (e.g. CD14, CR3 or SR), p38 and NFκB.

目錄
頁次
目 錄 1
圖 目 錄 IV
中 文 摘 要 VI
英 文 摘 要 VII
前 言 1
壹、小神經膠細胞 1
貳、壁脂酸 5
參、細菌毒素活化免疫細胞之可能訊息傳遞路徑 5
實驗目的 10
材料與方法 11
壹、細胞培養 11
貳、亞硝酸根濃度之測定 12
參、細胞存活率之測定 13
肆、iNOS的表現 13
伍、MAPKs及IB活性的的偵測 15
陸、雙重免疫螢光染色 16
柒、統計分析 17
結果 18
壹、LTA對初級培養中小神經膠細胞形態之影響 18
貳、LTA刺激初級培養中小神經膠細胞後，其不同濃度與時程對
細胞產生NO之影響 18
參、LTA刺激初級培養中小神經膠細胞後，其不同濃度與時程對
細胞存活率之影響 19
肆、LTA可刺激初級培養中小神經膠細胞產生增殖現象 19
伍、LTA刺激初級培養中小神經膠細胞後，其表面受體及免疫分
子之變化 19
陸、LTA刺激初級培養中小神經膠細胞產生NO的可能訊息傳遞
路徑 20
柒、LTA引發初級培養中小神經膠細胞產生NO的過程中，LTA
受體及p38與NFκB的關係 21
捌、LTA誘導初級培養中小神經膠細胞iNOS之表現 22
討論 24
結論 37
參考文獻 67
圖目錄
頁次
附圖一LTA活化小神經膠細胞產生NO其訊息傳遞路徑 38
圖1A-B. Morphological changes of unchallenged and LTA-atimulated microglia in vitro. 39
圖2A-B. NO accumulation and cell viability in cultured microglia challenged with LTA. 41
圖3A-B. NO accumulation and cell viability of isolated microglia after different intervals of LTA challenge. 43
圖4. Effect of LTA on the morphology of cultured microglial nuclei
labelled with DAPI. 45
圖5. Immunoblot analysis of proliferating cell nuclear antigen in
isolated microglia stimulated with LTA. 47
圖6. Immunoreactivities of complement receptor type 3 (CR3) and
CD14 receptor on isolated microglia after LTA challenge. 49
圖7. Immunoreactivities of major histocompability complex (MHC)
class II antigen and scavenger receptor (SR) on isolated
microglia following LTA treatment. 49
圖8. Effect of anti-CD14, CR3 or SR antibody on nitrite production
on LTA-stimulated microglia. 51
圖9. Immunoblot analysis of phosphorylated ERK, p38 and JNK
in microglia stimulated with LTA or vehicle. 53
圖10. Effects of MAPK and NFκB inhibitors on the production of nitrite
in cultured microglia exposed to LTA. 55
圖11. Effects of p38 inhibitors or antibodies of LTA receptors on lipoteichoic acid-induced IκB phosphorylation in cultured
microglial cells. 57
圖12. Effects of DMSO, mouse and rabbit immunoglobulin
fractions on nitrite production in LTA-stimulated microglia. 59
圖13. iNOS immunoreactivities of microglia following LTA treatment.61
圖14. Immunoblot analysis of iNOS induction in microglia and its
inhibition by anti-LTA receptors. 63
圖15. Immunoblot analysis of iNOS induction in cultured microglia
and its inhibition by MAPK or NFκB inhibitor. 65

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