背景：單核球細胞在受到革蘭氏陰性菌脂多醣 (LPS) 刺激時，會啟動脂多醣受器複合物 (CD14/TLR4/MD2) 辨識而引發先天性免疫反應。當LPS和細胞表面的CD14結合後，會活化脂質第二傳訊分子神經醯胺 (ceramide) 和PKCζ，以趨化鄰近的TLR4至脂筏上形成複合物，進而引發下游的訊息途徑包括MyD88、IκB-α及MAPK家族 (例如JNK、ERK和p38)。目前已知人類腸道上皮細胞之脂多醣受器分子的表現模式與免疫細胞相異，這是由於腸腔中有大量共生菌之存在，因此推測腸道上皮細胞具有屏障及抑制機制，以維持腸道生理恆定避免引起不必要之發炎反應。在我們先前的研究發現，於腸腔中給予LPS刺激，會誘導只有CD14而無TLR4表現之人類腸道上皮細胞株Caco-2的凋亡反應，且此凋亡過程是經由ceramide/PKCζ之途徑。因此本實驗目的為利用基因缺陷小鼠動物模式來探討腸腔面LPS和共生細菌增生的刺激是否會引發大腸上皮細胞之凋亡。材料與方法：使用野生型小鼠 (WT，BALB/c及C57C57BL/6)；TLR4基因自發性突變小鼠 (TLR4-m)；CD14基因特定突變 (基因剔除) 小鼠 (CD14-m)，取出其大腸組織放置在Ussing chambers上，於腸腔面給予PBS或LPS (萃取自非病原性大腸桿菌，5 and 50 μg/mL) 刺激2小時。利用缺口末端標記技術和細胞凋亡酵素免疫分析法測定腸道上皮細胞之凋亡程度，並使用免疫螢光組織染色和西方墨點法分析大腸黏膜組織 PKCζ、JNK、IκB-α及ERK磷酸化表現量。除此之外，將野生型和TLR4-m小鼠之大腸作假手術或腸阻塞處理24小時以誘發腸道細菌增生，再分析大腸黏膜細胞之凋亡程度，以及利用新鮮血液培養基和馬康氏培養基計數大腸、脾臟及肝臟之總細菌和G (-) 細菌之菌落形成單位 (CFU)。並且於Caco-2細胞株腸腔面加入活菌或死菌E.coli，測量其細胞凋亡與壞死量。結果：腸腔面LPS刺激會顯著引起TLR4-m小鼠之大腸上皮細胞凋亡，但對野生型BALB/c、C57BL/6及CD14-m小鼠之上皮細胞並無影響。預先投予中和性抗CD14抗體之抗體後和isotype control相比，可降低脂多醣刺激引起TLR4-m小鼠之大腸黏膜細胞凋亡程度。而在野生型BALB/c、C57BL/6和TLR4-m小鼠大腸腸腔面給予LPS刺激，會導致腸道上皮細胞PKCζ磷酸化表現量增加。此外，野生型C57BL/6和BALB/c之大腸黏膜組織受LPS刺激後，JNK及IκB-α磷酸化會上升，但這些現象並不見於CD14-m和TLR4-m小鼠組織上。再者，野生型BALB/c和TLR4-m小鼠在腸阻塞後，可觀察到腸道總細菌及G (-) 細菌量皆有顯著上升的情形，顯示大腸阻塞會導致腸道共生菌增生且此現象與鼠種並無直接相關性。腸阻塞處理後會造成野生型BALB/c小鼠腸道黏膜中的促發炎細胞激素 (TNF-α及IFN-γ) 表現增加，但TLR4-m小鼠無此表現。在野生型BALB/c小鼠作假手術或腸阻塞處理後，兩者黏膜細胞凋亡量並無差異；然而TLR4-m小鼠在腸阻塞後，大腸黏膜細胞凋亡量較假手術組增高三倍之多。且在野生型BALB/c及TLR4-m小鼠腸阻塞後可觀察到有PKCζ磷酸化表現於腸道上皮細胞。最後，野生型BALB/c和TLR4-m小鼠的肝臟及脾臟總細菌量，在腸阻塞後皆有上升的現象，顯示腸道屏障功能失常；而腸阻塞TLR4-m小鼠之肝脾總細菌量高出腸阻塞野生型BALB/c小鼠40倍。然而，兩鼠種的肝臟及脾臟之G (-) 菌量在假手術或腸阻塞組皆為0 CFU/g。最後，於Caco-2細胞株之腸腔面加入活菌或死菌E.coli會引起細胞凋亡且呈劑量依賴性。結論：在欠缺TLR4下游訊息傳遞的情況之下，腸腔面有LPS或共生菌增生的刺激會引發大腸上皮細胞之凋亡，且此過程可能是透過CD14/PKCζ媒介之途徑。

Background: Gram (-) bacterial lipopolysaccharide (LPS) induces innate immune responses via recognition by LPS receptor complex (CD14/TLR4/MD2) on cells of monocytic lineage. LPS binds to cell surface CD14 causing activation of a lipid secondary messenger ceramide and PKCζ to recruit adjacent TLR4 into lipid raft domains to form a receptor complex which initiates downstream signaling pathways including MyD88, IκB-α and MAPK families (e.g. JNK, ERK, and p38). In contrast to monocytes, distinct expression patterns of LPS receptors were identified in human enterocytes. The gut lumen normally harbors a large amount of commensal bacteria, for which barrier and suppressive mechanism at the epithelial level is important to downregulate unnecessary inflammatory reactions and to maintain gut homeostasis. Our previous studies indicated that luminal LPS triggered epithelial apoptosis via a ceramide/PKCζ-dependent pathway in human intestinal Caco-2 cells that express only CD14 but not TLR4 proteins. The aim of the current study is to investigate whether luminal LPS challenge and commensal bacteria overgrowth stimulate colonic enterocytic apoptosis in gene-deficient mouse models. Materials and methods: Wild type mice (WT; BALB/c and C57C57BL/6), mice with spontaneous mutation in TLR4 gene (TLR4-m), and mice with targeted mutation (knock out) of CD14 gene (CD14-m) were used. Mouse colonic tissues were mounted on Ussing chambers for luminal challenge with PBS or LPS (obtained from nonpathogenic E.coli; 5 and 50 μg/mL) for 2 hrs. The level of epithelial apoptosis was analyzed by TUNEL assay and cell death ELISA. Phosphorylation levels of PKCζ, IκB-α, JNK and ERK in the colonic mucosa were assessed by immunofluoresenct staining and western blotting. In the next experiment, colons of WT BALB/c and TLR4-m mice were either sham-operated or obstructed by thread ligation for 24 hrs to induce enteric bacterial overgrowth, and the apoptotic levels of colonic enterocytes were determined. Total and G (-) bacterial colony forming units (CFU) in the intestine, liver, and spleen was calculated on fresh blood and MacConkey agar plates. Caco-2 cells were apically exposed to live or dead nonpathogenic E.coli, and the levels of apoptosis and necrosis were examined. Results: Luminal LPS challenge significantly increased the levels of colonic epithelial apoptosis in TLR4-m mice, whereas no effect was seen in WT BALB/c, WT C57BL/6 and CD14-m mice. A slight decrease of LPS-induced mucosal apoptosis levels was seen in TLR4-m colonic tissues pretreated with neutralizing anti-CD14 compared with isotype antibody controls. LPS induced epithelial PKCζ phosphorylation in colonic tissues of WT BALB/c, C57BL/6 and TLR4-m mice. Enhanced mucosal phosphorylation of JNK and IκB-α was evident after luminal LPS challenge in WT C57BL/6 and WT BALB/c mice, but absent in CD14-m and TLR4-m mice. Moreover, colonic obstruction resulted in increase of total and G (-) bacterial counts in the intestines in both WT BALB/c and TLR4-m mice, suggesting obstruction-induced commensal bacterial overgrowth irrespective of mouse strain. Increased proinflammatory cytokines (TNF-α and IFN-γ) in intestinal mucosa was caused by colonic obstruction in BALB/c mice, but not in TLR4-m mice. No difference of mucosal cell apoptotic levels was seen between sham-operation and obstruction groups in WT BALB/c mice. However, a three-fold increase in mucosal cell apoptosis was evident in obstructed guts compared to sham operation in TLR4-m mice. Increased epithelial PKCζ phosphorylation was seen in the obstructed guts of WT BALB/c and TLR4-m mice. Enteric bacterial translocation was evidenced by increased total bacterial CFU in the liver and spleen after colonic obstruction in both WT BALB/c and TLR4-m mice, indicating gut barrier dysfunction. The total bacterial counts in the liver and spleen in obstructed TLR4-m mice were 40 times higher than those of obstructed WT BALB/c mice. However, G (-) bacterial counts in the liver and spleen after sham operation and colonic obstruction were 0 CFU/g in both mouse strains. Luminal challenge with live or dead E.coli induced Caco-2 cell apoptosis in a dose-dependent manner. Conclusions: Luminal LPS challenge and commensal bacterial overgrowth induced colonic epithelial cell apoptosis in mice deficient of TLR4 signaling. LPS-induced epithelial apoptosis may be mediated via CD14/PKCζ-dependent pathways.

口試委員審定書 I
謝辭 II
中文摘要 IV
Abstract VI
中英文縮寫名詞對照表 VIII
圖表目錄 XIV
一、前言 1
1. 腸道管壁之組織結構 1
2. 腸道之生理功能 1
2.1 消化 (digestion) 1
2.2 吸收 (absorption) 2
2.3 分泌 (secretion) 2
2.4 屏障 (barrier) 3
2.4.1 物理性屏障 (physical barrier) 3
2.4.2 化學性屏障 (chemical barrier) 3
2.4.3 免疫性屏障 (immune barrier) 4
3. 腸道上皮細胞之新生與凋亡 4
3.1 腺窩-絨毛軸 (crypt-villus axis) 4
3.2 上皮細胞過量凋亡會造成屏障缺損 4
3.3 上皮細胞低量凋亡與過量增生造成癌化現象 5
4. 細胞凋亡概論 5
5. 腸腔共生菌 (commensal bacteria) 與上皮細胞之互動 7
5.1 腸道共生菌概論 7
5.2 共生菌對腸道上皮細胞替換率 (turnover rate) 之影響 7
5.3 病理性共生菌增生與腸道發炎反應 8
5.3.1 細菌增生之臨床疾病 8
5.3.2 腸阻塞 9
6. 脂多醣受體複合物－TLR4、CD14、MD-2及其訊息途徑 10
6.1 脂多醣 (lipopolysaccharide, LPS) 10
6.2 脂多醣受體複合分子在單核球/巨噬細胞的表現 10
6.3 CD14媒介之下游訊息途徑 11
6.4 TLR4媒介之下游訊息途徑 12
6.5 CD14和TLR4在腸道上皮細胞之表現 14
6.5.1 正常人和病人腸道檢體之上皮細胞CD14和TLR4表現量 14
6.5.2 人類腸道上皮癌細胞株中的CD14和TLR4表現量和位置 14
6.5.3 小鼠腸道檢體上皮細胞中CD14和TLR4表現量和位置 15
6.5.4 小鼠腸癌上皮細胞株中CD14和TLR4表現量和位置 16
7. 脂多醣刺激對上皮細胞凋亡、發炎反應與癌化之關係 16
8. 研究目的 18
二、材料與方法 19
1. 實驗動物 19
2. 實驗設計 19
2.1 第一部分實驗：腸腔面大腸桿菌脂多醣刺激對上皮細胞凋亡的影響 20
2.1.1 腸組織架設於Ussing chambers 20
2.1.2 腸腔面大腸桿菌LPS的刺激 20
2.1.3 中和性抗CD14抗體 21
2.2第二部分實驗：大腸阻塞 (colonic obstruction, CO) 對於腸道功能之影響 21
2.3 第三部分實驗：活大腸桿菌 (E.coli) 及死大腸桿菌對於上皮細胞凋亡及壞死量和屏障功能之影響 22
2.3.1 細胞培養——人類大腸直腸癌之腸道上皮細胞株Caco-2 22
2.3.2 喜樹鹼 (camptothecin, CPT) 22
3. 組織切片及染色 23
3.1 檢體的製備 23
3.2 蘇木紫-伊紅染色 (Haematoxylin and Eosin Staining) 23
3.3 缺口末端標記技術 (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) 23
3.4 免疫螢光組織染色 (Immunofluorescence) 25
4. 細胞凋亡酵素免疫分析法 (Cell death ELISA kit) 26
4.1 腸道黏膜樣本之處理 26
4.2 測定細胞凋亡 (cell apoptosis) 26
5. 乳酸脫氫酵素 (Lactic dehydrogenase, LDH) 分析法 27
6. 腸段總細菌量 (total bacteria counts) 分析 27
7. 細菌移位測定 (bacterial translocation, BT) 28
8. 酵素連結免疫吸附分析法 28
9. 西方墨點法 (western blotting) 29
9.1 腸道黏膜之蛋白質萃取 29
9.2 蛋白質定量 29
9.3 蛋白質電泳 30
10. 統計分析 33
三、結果 34
第一部分實驗：腸腔面LPS刺激對小鼠腸道上皮細胞凋亡量之影響 34
1. 腸腔面LPS刺激會引發TLR4-m小鼠之腸道上皮細胞凋亡 34
2. 腸腔面LPS刺激引起小鼠腸道上皮細胞中訊息傳遞分子之改變 35
第二部分實驗：大腸阻塞 (colonic obstruction, CO) 和腸道細菌增生對於上皮細胞凋亡量和屏障功能之影響 36
1. 大腸阻塞對腸道細菌總數之影響 36
2. 大腸阻塞後黏膜細胞的凋亡程度 37
3. 大腸阻塞後黏膜組織TNF-a及IFN-r之產量 37
4. 大腸阻塞引起TLR4-m小鼠腸道上皮細胞中PKCζ之磷酸化 37
5. 大腸阻塞對屏障功能和細菌移位之影響 38
第三部分實驗：革蘭氏陰性大腸桿菌 (E.coli) 對上皮細胞凋亡及壞死量之影響 39
1. 腸腔面活菌E.coli的刺激會引起腸道上皮細胞株Caco-2之凋亡 39
2. 腸腔面死菌E.coli的刺激會引起腸道上皮細胞株Caco-2之凋亡 39
四、討論 40

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