白血球間素-17 (Interleukin-17, IL-17) 在宿主抵抗病菌中扮演關鍵角色。也有報導指出 IL-17 與自體免疫疾病病因有關。 IL-17為 Th17主要效應細胞激素， IL-23則可維持並擴大 Th17細胞群。對於 Th17細胞的 IL-23/IL-17訊息傳遞路徑已有相當多的研究。近年來越來越多的證據顯示，發炎反應的早期，許多先天免疫細胞會產生 IL-17，且這些細胞多位於與黏膜免疫有關的位置，如腸道、固有層、皮膚、肺等處。當這些先天免疫細胞感受到壓力、損傷或病原入侵時便會產生 IL-17。然而目前對於先天免疫細胞產生 IL-17的調控機制尚不十分清楚。我的研究重點為探討哪些轉錄因子參與調控噬中性顆粒球產生 IL-17。
我的實驗結果顯示未被刺激的 thioglycollate (thio)-elicited peritoneal cells 相較於 naive T 細胞表現較高量的 RORc、 AHR、 IL-23R 及 IL-6R。當 thio-elicited peritoneal cells 接受老鼠重組蛋白 IL-23刺激時，隨著刺激濃度增加、刺激時間增長， thio-elicited peritoneal cells 產生更多 IL-17A。但 IL-23的刺激並沒有增加 thio-elicited peritoneal cells 的 RORa、 RORc、 IRF-4或 AHR 的表現量，這些轉錄因子的 mRNA 表現量光是隨著培養時間增加就會上升。我將 thio-elicited peritoneal cells 利用 MACS 管柱區分為 Ly6G+ 及 Ly6G- 兩群細胞。 IL-23可促進 Ly6G+ 及 Ly6G- 兩群細胞產生 IL-17A，並伴隨著 RORc 的表現。
我比較野生型老鼠 (wild type, WT)、 STAT1 基因剔除鼠 (STAT1 knockout, STAT1 KO) 及 STAT3 基因剔除鼠 (STAT3 knockout, Mx-Cre+ STAT3flox/flox) 來探討噬中性顆粒球產生 IL-17A 時， STAT1 及 STAT3的參與情形。實驗結果顯示 IL-23刺激並不影響 STAT1 KO 或 STAT3 KO 細胞的 RORa、 RORc、 IRF-4和 AHR 表現量；但自 STAT1 KO 小鼠取得的 Ly6G+ 細胞接受 IL-23刺激後， RORa 表現量則比 WT 細胞低。
我亦以老鼠噬中性顆粒球細胞株 (MPRO) 作實驗，測試 MPRO 是否像初代細胞一樣經 IL-23刺激後會產生 IL-17A，以便將來可用以取代初代細胞來研究轉錄因子。我發現 ATRA 刺激後可誘導 MPRO 分化。受 ATRA 刺激的 MPRO 表現 Ly6G 並具有分葉的細胞核，且再接受 PMA 刺激後， MPRO 可產生 ROS。然而即便 ATRA 刺激後， MPRO 仍不表現 IL-23R。分化的 MPRO 接受 PMA 刺激後，再添加或不加 IL-23 刺激，依然不誘導 IL-17A 產生。
綜合上述，我的實驗結果顯示 IL-23誘導 thio-elicited peritoneal cells 以不須依賴 RORa、 RORc、 IRF-4 和 AHR 的方式產生 IL-17A，但是在未受 IL-23刺激的狀況下這些轉錄因子的 mRNA 就會隨著培養時間輕微上升。另外，Ly6G+ 及 Ly6G- 兩群細胞接受 IL-23刺激後，都會產生 IL-17A， 同時 RORc 表現量上升。與 Th17細胞相似，Ly6G+ 及 Ly6G- 兩群細胞當受 IL-23刺激後，均會以 RORγt 依賴方式產生 IL-17A。

Interleukin-17 (IL-17) mediates immune response and plays a crucial role in host defense against mucosal pathogens. It also contributes to the pathogenesis of autoimmune diseases. IL-17 was first discovered as an effector cytokine of Th17, and IL-23 maintains and expands the Th17 subset. The IL-23/IL-17 axis Th17 signaling pathway has been clearly defined. Recently, evidences showed that much of the IL-17 is produced by innate immune cells in the early phase of inflammation. Innate IL-17-producing cells are found to be in the mucosal tissues. They respond to stress, injury, or pathogens before Th17 cell differentiation. The mechanisms by which innate IL-17-producing cells produce IL-17 are still not clear. The aim of my study was to explore the transcription factor(s) involved in regulating neutrophil IL-17A production.
The results of my study showed that thioglycollate (thio)-elicited peritoneal cells expressed higher basal levels of RORc, AHR, IL-23R and IL-6R than naive T cells. Treatment of thio-elicited peritoneal cells with mouse recombinant IL-23 induced IL-17A production in a dose- and time-dependent manner. IL-23 stimulation did not enhance the expressions of RORa, RORc, IRF-4 or AHR. Rather, the mRNA of these transcription factors increased with time in culture. Thio-elicited peritoneal cells were separated into Ly6G+ cells and Ly6G- populations by MACS column. Both Ly6G+ cells and Ly6G- cells produced IL-17A upon stimulation by IL-23 and it was accompanied by an increase of RORc expression.
I compared thio-elicited peritoneal cells from wild type to STAT1 knockout (KO) and to STAT3 knockout mice (Mx-Cre+ STAT3flox/flox) to explore the involvement of STAT1 and STAT3 in neutrophil IL-17A production. The levels of RORα, RORγt, IRF-4 and AHR expression in STAT1 KO or STAT3 KO cells were not affected by IL-23 stimulation with the exception that the level of RORa expression was lower in Ly6G+ cells from STAT1 KO mice than those from wild type mice upon IL-23stimulation.
I also studied mouse neutrophil cell line MPRO IL-17A production after IL-23 stimulation in the hope of replacing primary cells by the cell line for transcription factor studies. I found that stimulation by ATRA induced MPRO differentiation. Stimulated MPRO expressed Ly6G, had segmented nucleus and produced ROS in response to PMA stimulation. However, MPRO did not express IL-23R even after ATRA stimulation. Pre-treatment of differentiated-MPRO with PMA did not induce IL-17A production with or without IL-23 stimulation.
In summary, I demonstrated in this study that IL-23 induced thio-elicited peritoneal cells to produce IL-17A independent of RORa, RORc, IRF-4 and AHR while the mRNA of these transcription factors increased slightly with time in culture even without IL-23 stimulation. Both Ly6G+ and Ly6G- cells stimulated by IL-23 produced IL-17A which was accompanied by RORc up-regulation. It appears that, both Ly6G+ and Ly6G- cells, like Th17 cells, produce IL-17A in a RORγt-dependent manner upon IL-23 stimulation.

致謝……………………………………………………………………………………....i
中文摘要…………………………………………………………………………….......ii
英文摘要……………………………………………………………………………......iv
目錄………………………………………………………………………………….….vi

第一章 緒論…………………………………………………………………………….1
(1) 白血球間素 IL-23及下游信號………………………………………………2
(2) 白血球間素 IL-17……………………………………………………….…... 3
(3) 噬中性顆粒球…………………………………………………………….......12
(4) 實驗動機與目的………………………………………………………….. …14

第二章 實驗材料與方法………………………………………………………...……15
第一部分………………………………………………………...………………......16
1. 實驗用老鼠……………………………………………...……………….......16
2. 抗體……………………………………………...………………...................16
3. 重組蛋白……………………………………………...………………...........17
4. 溶液……………………………………………...………………...................17
5. 化學藥劑和實驗器材…………………………………………...…………...22

第二部分 實驗方法…………………………………………...…………………..24
1. MPRO 繼代、分化及活化……………………………………...…………24
2. 邁格-吉薩姆染色法……………………………………...…………………24
3. 免疫螢光染色……………………………………...……………………….25
4. 分析 ROS 產量……………………………………...……………….…....25
5. 硫乙醇酸鹽誘導腹腔細胞 .……………………………………………….25
6. MACS 純化噬中性顆粒球………………………………….………..……25
7. Naive CD4 T 細胞的分選及 Th17 的分化…..……………………..……26
8. 流式細胞儀分析……………………………………...………………...…..26
9. 酵素連結免疫吸附分析法 (ELISA) ….………….…...……..……..…….27
10. 萃取 RNA 及反轉錄……………………...……………………………...27
11. 定量即時聚合酶鏈鎖反應………………………………………...……...27
12. 統計……………………………………………………………………......27

第三章 實驗結果………………………………………………………………….…..28
IL-23可刺激噬中性顆粒球產生 IL-17A…………………………...………..……29
IL-6 無法使 IL-23刺激的 thio-elicited peritoneal cells 產生更高量的
IL-17A………………………………………………………………..…...…………30
Ly6G+ 細胞及 Ly6G- 細胞被 IL-23刺激後RORγt 的表現量增加…………....30
在 IL-23刺激下 STAT1促使 thio-elicited peritoneal cells IL-17A的生成......…31
在 IL-23刺激下 STAT3抑制 thio-elicited peritoneal cells IL-17A的生成…..…33
誘導 MPRO 分化過程中，可觀察到細胞核逐漸多葉以及表現 Ly6G標誌……35

第四章 討論…………………………………………………………………………...37
IL-23 刺激 thio-elicited peritoneal cells 產生 IL-17A…………………………...38
IL-23 刺激使 Ly6G+ 細胞增加 RORγt mRNA………………………………......39
IL-23 刺激使Ly6G- 細胞增加 RORγt mRNA…………………………...…........41
STAT1和 STAT3調控 IL-23刺激 thio-elicited peritoneal cells 時 IL-17A 的
生成…………………………………………………………………...………..……42
MPRO 細胞株可分化為成熟具有功能的噬中性顆粒球…………………………45
參考文獻……………………………………………………………………………….47
圖表與說明…………………………………………………………………………….58

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