介白素-4與介白素-13調節乳腺細胞胰島素的訊息傳遞

第二型輔助型T細胞（T helper cell type II, Th2）之細胞激素如介白素（interleukin, IL）-4和IL-13主要是作用於白血球以調控免疫功能。然而，這兩種細胞激素亦能影響非血球細胞的諸多反應。懷孕時，體內環境偏向Th2以防止流產；同時Th2的環境也會促進乳腺的腺泡形成（alveologenesis）。此種形態發生是在既有的乳管上產生腺泡（acini），因而需要細胞大量的增生。我們以初代小鼠乳腺上皮細胞進行體外三維培養，發現IL-4和IL-13能促進細胞增生，造成腺泡變大；此現象是透過signal transducer and activator of transcription-6（STAT6）所致。在本篇研究，我們專注於胰島素受體受質-1（insulin receptor substrate-1, IRS-1），其為IL-4和IL-13訊息傳遞另一重要分子。我們的結果顯示，以IL-4和IL-13短暫處理乳腺細胞能刺激IRS-1的酪胺酸磷酸化，而長時間處理則會增加IRS-1的表現量並伴隨其酪胺酸磷酸化。因此，細胞在預處理IL-4和IL-13之後再給予胰島素能藉由提高IRS-1表現量而增強胰島素的訊息傳遞。另外，我們也發現IL-4和IL-13能刺激cyclin D1的表現量和基質金屬蛋白酶-9（matrix metalloproteinase-9）的活性，這可能介導了IL-4和IL-13所促進的細胞增生。總結而言，本篇研究結果顯示IL-4/IL-13與胰島素訊息傳遞產生交流（crosstalk），我們推測可能藉此幫助乳腺的發育。

T helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, a bias of Th2 environment prevents abortion, and at the same time, facilitates alveologenesis of mammary glands. This particular morphogenesis generates alveoli from existing ducts that requires substantial extents of cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we have found that IL-4 and IL-13 greatly promote cell proliferation, leading to enlargement of mammary acini. This mitogenic effect is mediated by STAT6. Here we focused our studies on insulin receptor substrate-1 (IRS-1), another key signaling molecule involved in IL-4 and IL-13 signaling. Our results showed that short exposure of IL-4 or IL-13 stimulated tyrosine phosphorylation of IRS-1, but prolonged exposure enhanced IRS-1 expression with a concomitant increase in its tyrosine phosphorylation. Accordingly, pretreatment of IL-4 or IL-13 augmented insulin signaling by elevating IRS-1 expression. We also found that IL-4 and IL-13 stimulated expression of cyclin D1 and activation of matrix metalloproteinase-9 (MMP-9), which might confer the effect of IL-4 and IL-13 on cell proliferation. Taken together, our results suggest a crosstalk between IL-4/IL-13 and insulin signaling, which may help mammary gland development.