- 學位論文
介白素-4與介白素-13對乳腺上皮細胞生理反應之影響
Effect of intereleukin-4 and interleukin-13 on physiological responses of mammary epithelial cells
摘要
介白素-4(interleukin-4, IL-4)和介白素-13(interleukin-13, IL-13)是第二型輔助型T細胞所分泌的細胞激素，具有廣泛的功能。它們不僅控制免疫反應，還調節複雜的組織生理。在乳腺中，IL-4和IL-13促進懷孕期間的腺泡生成，這種特殊的形態變化需要產生大量的細胞增殖。我們使用初代小鼠乳腺上皮細胞進行體外的3D培養，發現IL-4和IL-13能刺激細胞增殖以及乳蛋白-乙型酪蛋白(β-casein)的表達。這是由IL-4/IL-13信號途徑的信號分子STAT6所介導。在本篇研究中，我們探討在IL-4/IL-13刺激的反應中營養素代謝所扮演的角色。由營養素剝奪的實驗結果得知細胞增殖需要麩醯胺酸，而乙型酪蛋白的合成則是更依賴於葡萄糖。這些結果顯示不同營養素之間的分工似乎是為了在乳腺細胞中執行不同的功能。我們也探討IL-4/IL-13信號傳導的另一信號分子-胰島素受體受質-1(Insulin receptor substrate 1,IRS-1)對細胞增殖和乙型酪蛋白合成的影響。IRS-1抑製劑NT157能抑制細胞增殖，表明IRS-1在增殖中的正向作用。因此，IL-4和IL-13通過協調不同的信號途徑和營養代謝來促進乳腺功能。
並列摘要
Interleukin (IL)-4 and IL-13, belong to T helper (Th)-2 cytokines, exert a wide spectrum of functions. They not only control immune responses but also regulate complex tissue physiology. In mammary glands, IL-4 and IL-13 promote alveologenesis during pregnancy. This particular morphogenesis needs substantial cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we have discovered that IL-4 and IL-13 stimulate cell proliferation as well as expression of the milk protein β-casein. These events are mediated by STAT6, the major signaling molecule of the IL-4/IL-13 signaling pathway. In this study, we examined the involvement of nutrient metabolism in IL-4/IL-13-stimulated responses. Results of nutrient deprivation revealed that cell proliferation requires glutamine, whereas β-casein synthesis relies more on glucose. There seems to be a division of labor between different nutrients to fulfill distinct functions in mammary cells. We also inspected the requirement of insulin receptor substrate (IRS)-1, another signaling molecule for IL-4/IL-13 signaling, for cell proliferation and b-casein synthesis. Application of IRS-1 inhibitor NT157 suppressed cell proliferation, suggesting a positive role of IRS-1 in proliferation. Thus, IL-4 and IL-13 promote mammary functions through coordination of different signaling pathways and nutrient metabolism.