發炎性腸道疾病(inflammatory bowel disease) 是一種長期慢性發炎的疾病，這種疾病會造成疼痛、嘔吐、腹瀉、直腸出血和體重減輕。前胸腺素(prothymosin α)是一種高度酸性且廣泛存在各種生物中的蛋白，涉及多種細胞內和細胞外功能，如細胞增殖、凋亡、氧化壓力和免疫調節等功能。我們實驗室先前的研究發現前胸腺素過度表達在肺氣腫的致病機制佔有重要角色，其機制是透過增加NFκB和Smad7的乙醯化 (acetylation)，最後會導致NFκB的活化以及抑制transforming growth factor-β (TGF-β)的訊號傳導。過去研究發現TGF-β訊號傳導能促進regulatory T (Treg)以及T helper 17 (Th17)細胞的分化，而由Th17所產生的interleukin-17 (IL-17)也被認為在發炎性腸道疾病中具有維持腸道上皮細胞中緊密連接蛋白(tight junction protein)的完整性。因此我們推測前胸腺素可透過抑制TGF-β之訊號傳導，而減少Treg和Th17細胞的分化，導致發炎性腸道疾病更為嚴重。在本研究中，我們利用葡聚糖硫酸鈉(dextran sodium sulfate，DSS)在C57BL/6小鼠誘導結腸炎的模式模擬人類發炎性腸道疾病，探討前胸腺素是否可透過損害腸道上皮細胞屏障的完整性，而在結腸炎致病機制中扮演角色，且前胸腺素是否可作為治療的標的。我們發現在DSS誘導結腸炎的小鼠其前胸腺素的表現量在第七天有顯著增加，且其表現量似乎和結腸炎的嚴重程度呈現正相關。以DSS誘導結腸炎之前胸腺素轉殖基因小鼠中，亦發現結腸中IL-17A的mRNA與野生型小鼠相比有較低的表現。值得注意的是DSS誘導結腸炎之小鼠以抗前胸腺素的單株抗體治療，可減緩結腸炎的症狀，且結腸中IL-17A的mRNA有上升的現象，而腸道上皮細胞的通透性也有降低的結果。p38及JNK的磷酸化被認為能夠維持穩定腸壁細胞的功能，在SW480大腸癌細胞過度表達前胸腺素的實驗中，我們也觀察到由IL-17引起的下游反應，包括p38及JNK的磷酸化有明顯地下降；觀察緊密連接蛋白中的封閉蛋白(occludin)也確實有減少的趨勢。總結本研究的結果，我們發現前胸腺素除了會抑制TGF-β訊號外，也會降低腸道上皮細胞屏障的完整性，而在發炎性腸道疾病致病機制中扮演角色；我們的研究結果亦顯示前胸腺素可作為治療發炎性腸道疾病的標的。

　　Inflammatory bowel disease (IBD) is a chronic inflammatory disease that causes abdominal pain, vomiting, diarrhea, rectal bleeding, and weight loss. Prothymosin α (ProT) has diverse biological functions, such as cell proliferation, apoptosis, oxidative stress, and immunomodulation. We have shown that ProT contributes to emphysema pathogenesis through inhibiting TGF-β signaling. TGF-β signaling can promote regulatory T (Treg)/T helper 17 (Th17) cell differentiation. IL-17 produced by Th17 cells can maintain intestinal epithelial barrier for tight junction formation in IBD. As ProT can inhibit TGF-β signaling, we hypothesized that it may downregulate Treg and Th17 cell differentiation and cause IBD. In this study, we used a C57BL/6 mouse model of dextran sodium sulfate (DSS)-induced colitis resembling human IBD to investigate whether ProT played a role in colitis pathogenesis and could serve as a therapeutic target. Our results show that expression of ProT was positively correlated with the degree of colitis severity. Furthermore, ProT transgenic mice treated with DSS expressed lower levels of IL-17A mRNA compared with their control counterparts. Notably, treatment of mice with anti-ProT monoclonal antibody during DSS induction ameliorated colitis symptoms, reduced colon epithelial cell permeability, and increased colon IL-17A mRNA levels. Overexpression of ProT in SW480 colon cancer cells reduced occludin expression and inhibited IL-17 downstream signaling, including p38 and JNK phosphorylation. Collectively, our results demonstrate that in addition to the inhibition of TGF-β signaling, ProT can reduce the intestinal epithelial barrier integrity and thereby contribute to the pathogenesis of IBD. Furthermore, ProT may be a therapeutic target for IBD.

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