干擾素-γ對乳腺細胞構形及功能的影響

乳腺的關鍵功能在於分泌乳汁。要達到最佳的泌乳需要適當的乳腺發育，而這需要由各種激素和生長因子精準的調控。近年來的研究發現一些免疫因子也參與其中，例如細胞激素。第二型輔助T細胞(Th2)的細胞激素-介白素-4(interleukin-4, IL-4)和介白素-13(interleukin-13, IL-13)已顯示可在懷孕期間促進腺泡的生成，然而第一型輔助T細胞(Th1)的細胞激素-干擾素-γ(interferon-γ, IFN-γ)，則會對青春期乳管的生長和分支等形態改變進行負調節的作用。有鑑於感染或發炎反應可能使Th1/Th2的平衡朝向Th1，使得IFN-γ和腫瘤壞死因子(tumor necrosis factor-α,TNF-α)的水平會升高，所以我們想知道Th1細胞激素是否會妨礙乳腺發育並導致泌乳失調。使用初代小鼠乳腺上皮細胞進行體外3D培養，我們發現IFN-γ會抑制泌乳激素所誘發的STAT5酪胺酸磷酸化和乙型酪蛋白(β-casein)的表現，而乙型酪蛋白這一乳蛋白的表現反映了乳汁產生和細胞分化的程度。IFN-γ還會增強細胞凋亡並破壞乳腺腺泡的組織結構，從而導致內腔充填。由於胰島素能促進乙型酪蛋白最佳的表現和乳腺細胞的存活，我們檢測Th1細胞激素對胰島素受體（insulin receptor, IR）和胰島素受體受質-1（insulin receptor substrate-1, IRS-1）表現的影響。IFN-γ降低了IRS-1的表現量，但不影響IR的表現量。除泌乳激素外，IL-4也會刺激乙型酪蛋白表現。IFN-γ會抑制IL-4誘導乙型酪蛋白的表現。TNF-α也造成了相似的結果，但其作用不如IFN-γ明顯。綜上所述，我們的結果推測由感染或發炎造成的Th1環境可能導致泌乳功能不全。

關鍵字

干擾素-γ

並列摘要

The key function of mammary glands is to produce milk. Optimal lactation requires proper development of mammary glands, which is delicately controlled by various hormones and growth factors. Emerging players are immune mediators such as cytokines. The T helper (Th)2 cytokines, interleukin (IL)-4 and IL-13, have been shown to facilitate alveologenesis of mammary glands during pregnancy, whereas the Th1 cytokine, interferon (IFN)-γ, negatively regulates ductal growth and branching morphogenesis during puberty. Given that infection or inflammation could tip the Th1/Th2 balance toward a Th1 milieu with high levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α, we wonder if Th1 cytokines could jeopardize mammary gland development, leading to lactation failure. Using 3D cultures of primary mouse mammary epithelial cells, we found that IFN-γ inhibited prolactin-induced STAT5 tyrosine phosphorylation and expression of β-casein, a milk protein whose expression reflects the degree of milk production and cell differentiation. It also enhances cell apoptosis and disrupted structural organization of mammary acini, resulting in luminal filling. Since insulin promotes optimal β-casein expression and survival of mammary cells, we examined the effect of Th1 cytokines on expression of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1). IFN-γ lowered IRS-1 levels without changes in IR abundance. In addition to prolactin, IL-4 stimulates β-casein expression. IFN-γ inhibited IL-4-induced β-casein expression. Similar results were obtained for TNF-α, but its effects were less pronounced than those of IFN-γ. Taken together, our results suggest that a Th1 milieu generated by infection or inflammation might lead to lactation insufficiency.

並列關鍵字

interferon-γ

參考文獻

Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T L., Murphy, KM., 2002. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat. Immunol. 3, 549-557.

Google Scholar

Akhtar, N., Streuli, C.H., 2006. Rac1 links integrin-mediated adhesion to the control of lactational differentiation in mammary epithelia. J. Cell Biol. 173,781-793.