- 學位論文
介白素-4對乳腺細胞增生與分化之影響
Effect of Interleukin-4 on proliferation and differentiation of mammary epithelial cell
摘要
懷孕時乳腺結構產生巨大的變化，即在原有之乳管上產生腺泡，腺泡細胞再分化因而具備合成乳汁的能力。許多荷爾蒙和生長因子皆參與調節此時期的發育。近來的文獻指出，第二型輔助型T細胞（Th2）細胞激素對於懷孕期乳腺的發育扮演了重要的角色，因為懷孕時體內環境是偏向於Th2以防止母體對胎兒的排斥。基於此因，我們對Th2細胞激素在乳腺發育的角色倍感興趣，尤其是介白素-4（interleukin-4；IL-4）。在本篇研究中，我們發現培養在基底膜基質（basement membrane）的乳腺細胞受到IL-4刺激後能夠表現乙型酪蛋白（β-casein），此基因常被用來當作乳腺細胞分化的指標。與泌乳激素相同，IL-4誘發乙型酪蛋白的表現是需要細胞黏附於基底膜。然而，IL-4所誘發的STAT6酪胺酸磷酸化並不需要，顯示啟動乙型酪蛋白的表現不只需要STAT6，還需要來自基底膜基質的訊號。在缺乏基底膜時，像是將細胞培養在一般的塑膠盤，IL-4僅能略為刺激乙型酪蛋白的表現，但抑制RhoA訊息路徑能提升其表現。IL-4刺激的細胞呈現一顯著表型，即乳腺腺泡明顯變大。這些細胞表現高量的proliferation cell nuclear antigen（PCNA）以及納入大量的5-ethynyl-2’-dexoyuridine（EdU），顯示了IL-4具有刺激細胞增生的能力。此外，IL-4能提高胰島素受體受質-1（insulin receptor substrate-1）的蛋白質表現量，進而加強胰島素的訊息傳遞。因此，IL-4不僅作用於免疫系統，也能調控乳腺細胞的增生與分化。
並列摘要
During pregnancy, mammary glands undergo massive changes in their structures with the appearance of alveoli in the existing ducts. The luminal alveolar cells are then differentiated and acquire the ability to synthesize and secrete milk. This is delicately controlled by various hormones and growth factors. The emerging players for mammary gland development during pregnancy are T helper (Th)2 cytokines. since a Th2 bias is formed during pregnancy to prevent rejection of the fetus by the mother. We are thus interested in the role of Th2 cytokines in mammary gland development, especially interleukin-4 (IL-4). Here we found that IL-4 alone stimulates expression of the milk protein β-casein, a marker gene for differentiation, in mammary cells cultured on a reconstituted matrix of basement membrane (BM). Similar to prolactin, cell adhesion to BM is obligatory for induction of this gene. However, tyrosine phosphorylation of Stat6, the upstream signaling event of IL-4 signaling, is activated irrespective of the type of matrix, suggesting that Stat6 activity is not sufficient, and other signals elicited by cell-BM interactions are needed. For cells that are devoid of proper adhesion to BM such as culturing on tissue culture plastic, β-casein expression is weakly induced by IL-4 but can be enhanced by inhibition of the RhoA pathway. A striking feature in cells treated with IL-4 is the enlargement of mammary acinus. These cells express higher levels of proliferation cell nuclear antigen (PCNA) and incorporated higher amounts of 5-ethynyl-2’-deoxyuridine (EdU) than untreated cells, implying that IL-4 stimulates cell proliferation. IL-4 also augments the expression of insulin receptor substrate (IRS)-1 and boosts insulin signaling. Thus, IL-4 regulates not only immune functions but also cell proliferation and differentiation in mammary glands.
參考文獻
延伸閱讀
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