IL-12 是調控 Th1 發展與細胞性免疫的關鍵細胞激素,它是由 p40 與 p35 次單元組成的二聚體。在 CD4+ T細胞中, IL-12 透過 JAK-STAT訊號傳遞途徑使 STAT4 氨酸磷酸化成為活化的轉因子而引發相關基因表現,如γ干擾素基因,使細胞分化為 Th1 活化毒性 T細胞及巨噬細胞。正因為 IL-12 在免疫調節上的重要性,許多研究指出 IL-12 可以有效治病毒感染、風濕性關節炎等某些自體免疫疾病、甚至是癌症。最近,透過基因序資之比對,科學家們找出和 IL-12p35 結構相似的個蛋白質 p19 和 p28 。 p19 可以和 IL-12p40 結合而形成 IL-23,而 p28 則和 EBI3 結合形成 IL-27。 IL-27、 IL-12 與 IL-23 因為結構上的相似性而被視為同一家族的細胞激素,它們的功能也被證實皆可調控 Th1 發展,但是和 IL-12 比較起, IL-23 只作用在記憶細胞,而 IL-27 主要作用於 Th1 分化的初始階段,因此這三個細胞激素似乎對 Th1 的發展有階段性的貢獻。在治應用上,而我們去也報告指出 IL-23 和 IL-12 一樣也同樣具有抗癌與抗轉移的功效,並可激小鼠對癌細胞產生免疫記憶。然而到目前為止,我們並清楚 IL-23 或是 IL-27 在 CD4+ T細胞中的訊號傳遞途徑,及它們調控 Th1 分化的分子機制。本計畫以短干擾 RNA(siRNA)抑制 CD4+/CD45RBlow T細胞中 STAT4 的表現,發現會因此阻斷細胞對 IL-23 之反應,顯示 STAT4 對此細胞激素訊號傳遞過程中的必要性。
Interleukin-12 (IL-12), which is composed of a p35 and a p40 subunit, is a proinflammatory natural-kill cell-stimulating, Th1-inducing and Th1-maintaining cytokine, which promote cell-mediated immunity. These biological functions make IL-12 a potent therapeutic agent for virus infection, malignant diseases, and autoimmune diseases. The JAK-STAT pathway has been demonstrated to be activated by IL-12 and play an important role in IL-12 signaling. IL-12-dependent synthesis of IFN- ?^ induction, T cell proliferation, and natural killer activation requires the activity of the transcription factor STAT4. Recently, it is reported that p40 can be covalently linked to a p35-related protein p19. This heterodimer is known as IL-23 and has activities on memory T cells. IL-27 is a heterodimer composed of the p40-related protein EBI3 (Epstein?VBarr virus-induced gene 3) and the p35-related protein p28. IL-27 is involved in early Th1 initiation.However, the molecular mechanism underlay the signal transduction of IL-23 or IL-27 remains unclear. It will be important to determine how IL-23/IL-27 integrates into the IL-12 family with regard to its function in Th1 development. In this study, the role of STAT4 in IL-23 signal transduction had been examined.