臺灣博碩士論文加值系統

中文摘要

長期性細菌感染以及常見性感染是糖尿病患者主要的併發症之一，這兩者皆與發炎細胞之活化具有相關聯性。然而，長期高濃度葡萄糖對於巨噬細胞活化作用，卻無太多相關性的研究。
因此，本研究以 LPS 刺激 RAW 264.7 巨噬細胞，作為一個實驗的模型，再以 15 mM 高濃度葡萄糖培養液去探討不同的培養時間，與正常 DMEM 培養下的 RAW 264.7 巨噬細胞，分別對於 LPS 刺激後的情形。實驗結果發現，RAW 264.7 巨噬細胞在15 mM 高濃度葡萄糖培養 1 天（急性）， 7 天（中慢性）和 14 天（慢性） 之後，basal NO 產生量會比正常細胞的多，而 LPS 刺激的 NO 產量卻明顯不如正常細胞。然而，在 iNOS protein 與 iNOS mRNA 的表現上，經長期慢性培養後，卻有反彈性大量增加的情形。
添加 15 mM 葡萄糖培養液培養 1 天及 14 天的 RAW 264.7 巨噬細胞，於 LPS 刺激後所產的促發炎細胞激素 TNF-a，與正常 DMEM 培養的細胞相比較是沒有明顯差異。不過，LPS 刺激的 TNF-a 產量在經過 15 mM 葡萄糖培養液培養培養 7 天後的巨噬細胞卻明顯比正常 DMEM 培養的細胞的產量少。15 mM 葡萄糖培養後的 RAW 264.7 巨噬細胞，所產生的 IL-1 b 產量在 basal 值與正常 DMEM 培養的細胞相比，均有明顯大量誘發的情形。培養 1 天及 14 天 15 mM 高濃度葡萄糖，在添加 LPS 刺激後，所產生的 IL-1 b 濃度與正常 DMEM 培養的細胞相比，有較為明顯上升的情形。然而，在 IL-6 的表現量方面，經 LPS 刺激 15 mM 高濃度葡萄糖培養 1 天後的 RAW 264.7 巨噬細胞，與正常 DMEM 培養的細胞相比，有著明顯上升的情形。有趣的是，在培養 7 天後，IL-6 的產量有被抑制的情況，而 14 天高葡萄糖培養後，卻又有一個回升的現象。
然而造成這些結果的原因，可能與細胞隨著高濃度葡萄糖長期培養後，而產生適應性和一個生理弁鄐W正向調節 ( up-regulation ) 的情形。隨著葡萄糖培養之 RAW 264.7 巨噬細胞，經由 LPS 活化細胞後，所誘發的促發炎細胞激素 ( TNF-a, IL-6, IL-1 b ) 皆與 iNOS protein 和 iNOS mRNA 的表現有著正相關性。

關鍵字：糖尿病、一氧化氮、發炎反應、高血糖症、細胞激素

Abstract

　　One of major complications of diabetes is the frequency of infection and long-term duration of bacterial infections. Both conditions have been shown to be related to activation of inflammatory cells. However, the influences of macrophage activation by long-term exposure to high glucose, a situation that mimics the hyperglycemia of diabetics, have not been fully investigated.
　　We used a lipopolysaccharide ( LPS ) activated macrophage RAW 264.7 model to investigate effects of acute ( 1 day ), sub-chronic ( 7 days ), and chronic ( 14 days ) 15 mM glucose treatment on activation of inflammatory cells. Basal NO production was higher in all glucose treated groups than that produced in normal cells. In contrast, LPS-induced NO production was sustained lower in the glucose treated cells than in the normal group. Interestingly, LPS-stimulated iNOS protein or iNOS mRNA expression in chronic glucose treated cells showed a more condensed bend than acute, sub-chronic or normal cells.
　　Treatment of RAW264.7 macrophages with 15 mM glucose for 1 and 14 days did not affect LPS-stimulated tumour necrosis factor-alpha ( TNF-a ) production. However, the same treatment for 7 days suppressed TNF-a production. Basal interleukin-1 beta (IL-1b) was increased significantly in high glucose treatment groups than that in normal control group. LPS-stimulated IL-1 productions were also increased except for 7-day treated group. Acute glucose challenge induced both basal and LPS-stimulated interleukin-6 ( IL-6 ) production. These increases were both suppressed in sub-acute groups. Interestingly, chronic glucose treatment did not affect basal IL-6 production but the production was raised the LPS-stimulated condition.
　　These results shown that may be due to an up-regulation or adaptation change after cells exposed to glucose chronically. Pro-inflammatory cytokines, TNF-a, IL-1b, and IL-6 that mediate the activation of macrophage via LPS stimulation, are also shown a similar adaptive pattern as iNOS protein and mRNA expression in responding to glucose treatment.

Key words: Diabetes, Nitric Oxide ( NO ), inflammation, Hyperglycemia, cytokines ( TNF-a, IL-1 b, IL-6 ).

目 錄 頁次

中文摘要………………………………………………………………I
英文摘要……………………………………………………………...III
本文目錄.……………………………………………………………...V
縮寫表……………………………………………………………….VIII

第一章、緒論………………………………………………………….1
1-1. 糖尿病相關研究………………………………………………1
1-2. 糖尿病的定義…………………………………………………2
1-2-1. 糖尿病的診斷……………………..………………………...2
1-2-2. 糖尿病的分類………………..……………………….……..3
1-2-3. 糖尿病之流行病學……………………………………...…..4
1-3. 糖尿病與感染……………………………………………….....5
1-3-1. 糖尿病與其細胞免疫調節………..………………………....6
1-3-2. 免疫反應與巨噬細胞……………..…………………………7
1-3-3. 細菌內毒素與巨噬細胞…………..…………………………7
1-3-4. 發炎反應與巨噬細胞……………..…………………………8
1-3-5. 一氧化氮 ( Nitric Oxide )…………..………………………..8
1-3-6. 腫瘤壞死因子 ( TNF-a )………….…………………………9
1-3-7. 介白素-1 ( IL-1 )…………..…..…………………………….10
1-3-8. 介白素-6 ( IL-6 )……………………..……………………...10
1-3-9. 一氧化氮合成酶 ( iNOS )…..………………..………….......11
1-4. 研究動機…………..…………………………………...………12

第二章、材料與方法……………………………………………..........14
2-1. RAW 264.7 巨噬細胞之培養……………………………........14
2-1-1. RAW 264.7 巨噬細胞之繼代培養………………………….15
2-1-2. RAW 264.7 巨噬細胞之冷凍..……………………………...16
2-1-3. RAW 264.7 巨噬細胞之解凍..…….......................................17
2-2. 15 mM 高葡萄糖 DMEM 培養 RAW 264.7 巨噬細胞...…….17
2-3. 細胞計數 / 種植細胞..……..……………………………….….18
2-4. 亞硝酸鹽產物測定……………………………………....…….19
2-5. TNF-a 濃度測定……………………...……………………….20
2-6. IL-1 b 濃度測定…………...…………….…………………….23
2-7. IL-6 濃度測定………...……….………………………….........25
2-8. 蛋白質抽取……………………………….…………….….......27
2-9. 蛋白質濃度測定…… …………..……………………….…….28
2-10. 西方墨點法 ( Western Blot )………..………..……….……...29
2-11. RNA 抽取………………..……..…………………….………31
2-12. 反轉錄-聚合酶鏈反應 ( RT-PCR )……..……………………33
2-13. DNA 瓊膠製備/ DNA 電泳…………..……………….……..34
2-14. 統計方法………………………………………………...........35

第三章、結果……………………………………………………..........36
3-1. NO產量試驗……..……………………………………..…......36
3-2. iNOS protein assay by Western Blot...………………….…......37
3-3. iNOS mRNA expression by RT-PCR.………..……….…….....37
3-4. TNF-a 產量試驗.…………..…………………………….........38
3-5. IL-6 產量試驗..…...……………………………………............39
3-6. IL-1 b 產量試驗……..………….………………………..........39

第四章、討論…………………………………………………………..41

第五章、結論…………………………………………………………..45

參考文獻………………………………………………………………..46

附錄……………………………………………………………………..60
圖1.a 1 day glucose treatment on basal NO production……………......60
圖1.b 1 day glucose LPS stimulated NO production………………......61
圖1.c 7 day glucose treatment on basal NO production……………......62
圖1.d 7 day glucose LPS stimulated NO production…………..............63
圖1.e 14 day glucose treatment on basal NO production………………64
圖1.f 14 day glucose LPS stimulated NO production……………….....65
圖2.a iNOS protein on basal expression by Western Blot……………..66
圖2.b iNOS protein on LPS stimulated expression by Western Blot…..67
圖3.a iNOS mRNA expression by RT-PCR……………………………68
圖4.a Effect glucose treatment on basal TNF-a production…………...69
圖4.b Effect glucose treatment on LPS stimulated TNF-a production...70
圖5.a effects of glucose treatment on basal IL-6 production……..........71
圖5.b effects of glucose treatment on LPS-stimulated IL-6 production.72
圖6.a effects of glucose treatment on basal IL-1 b production…............73
圖6.a effects of glucose treatment on LPS stimulated IL-1 b production74

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