第二型輔助T細胞(Th2)細胞激素─介白素-4(interleukin-4, IL-4)和介白素-13(interleukin-13, IL-13)除了參與宿主防禦外還有其他功能。在懷孕期間，IL-4和IL-13刺激乳腺的腺泡形成(alveologenesis)。這種特殊的生長形態需要透過細胞大量增生才能在原先的乳管上形成腺泡。我們以3-D模式培養初代小鼠乳腺上皮細胞發現IL-4和IL-13能刺激乳腺細胞增生，導致腺泡變大。而此現象並不依賴葡萄糖的代謝，因為移除葡萄糖對於細胞增生影響不大。相反，降低麩醯胺酸濃度和抑制麩醯胺酸酶的活性造成IL-4和IL-13刺激的細胞增生減少，這表明了麩醯胺酸的代謝參與Th2細胞激素誘發的細胞生長。檢測相關訊息傳遞機制發現這涉及了IL-4和IL-13訊息傳遞的關鍵分子，STAT6。而另一個訊息傳遞分子─胰島素受體受質-1(insulin receptor substrate-1)，其表現量在長時間的IL-4或IL-13處理後增強。IRS-1不僅參與基態的(basal state)細胞增殖也影響IL-4和IL-13所誘發的增生。因此，懷孕期間體內趨向Th2的環境可透過訊號傳導與代謝的協調提高細胞增生來促進乳腺的正常發育。 The T helper (Th)-2 cytokines, interleukin (IL)-4 and IL-13, have functions beyond host defense. They promote alveologenesis of mammary glands during pregnancy. This particular morphogenesis requires extensive cell proliferation to generate alveoli from existing ducts. Using 3D cultures of primary mouse mammary epithelial cells, here we found that IL-4 and IL-13 stimulated cell proliferation, leading to enlargement of mammary acini. This mitogenic effect did not rely on glucose metabolism since glucose deprivation exerted minimal influences on cell proliferation. By contrast, lowering glutamine concentration and inhibition of glutaminase activity resulted in a decrease in IL-4- and IL-13-stimulated cell proliferation, suggesting that glutamine metabolism supports Th2 cytokine-elicited cell growth. Examination of underlying signaling mechanisms revealed that STAT6, the key molecule for IL-4 and IL-13 signaling, was involved. The other signaling molecule, insulin receptor substrate (IRS)-1, whose expression was enhanced in response to prolonged treatment of IL-4 and IL-13 was not only required for basal state but also IL-4- and IL-13-stimulated cell proliferation. Therefore, a Th2 milieu during pregnancy might confer mammary gland development by promoting cell proliferation via coordinated signaling and metabolism.
