1、簡介

干擾素（IFN）多效性細(xì)胞因子家族，根據(jù)受體特異性可分為三型：I型（含IFN-α/β等13個亞型，通過IFNAR1/IFNAR2受體傳遞信號）、II型（僅包含IFN-γ，特異性結(jié)合IFNGR1/IFNGR2受體）及III型（IFN-λ，依賴IL-10R2/IFNLR1受體發(fā)揮作用）^[1-2]。IFN-γ是Ⅱ型干擾素的成員，其基因定位于人類染色體12q15區(qū)域，包含4個外顯子，其編碼基因在脊椎動物中呈現(xiàn)高度保守性（人鼠氨基酸序列同源性約70%）。編碼的成熟蛋白由143個氨基酸通過鏈間二硫鍵形成功能性同源二聚體，其受體結(jié)合域中保守的α螺旋結(jié)構(gòu)對生物活性至關(guān)重要^[3]。

IFN-γ主要由T淋巴細(xì)胞、自然殺傷細(xì)胞（NK）和抗原提呈細(xì)胞（APCs，包括單核細(xì)胞、巨噬細(xì)胞和樹突狀細(xì)胞）分泌^[4-6]。其表達(dá)受先天免疫信號的嚴(yán)格調(diào)控，APCs通過分泌IL-12/IL-18激活STAT4/NF-κB通路，一方面趨化NK細(xì)胞向炎癥部位遷移，另一方面直接誘導(dǎo)IFN-γ基因轉(zhuǎn)錄，形成連接病原識別與適應(yīng)性免疫啟動的關(guān)鍵調(diào)控軸^[7-9]。

作為免疫微環(huán)境的核心調(diào)控者，IFN-γ在感染部位呈現(xiàn)爆發(fā)式表達(dá)特征，其通過激活巨噬細(xì)胞殺菌功能、上調(diào)MHC分子表達(dá)及驅(qū)動Th1分化等機制增強宿主防御^[10]。同時，該因子在腫瘤免疫中發(fā)揮雙重作用：既可誘導(dǎo)腫瘤細(xì)胞免疫原性死亡，又能促進(jìn)免疫檢查點分子（如PD-L1）表達(dá)形成負(fù)反饋調(diào)控^[11]。這種功能復(fù)雜性與其獨特的信號級聯(lián)機制直接相關(guān)，IFN-γ通過結(jié)合異源二聚體受體（IFNGR1/IFNGR2），觸發(fā)JAK1/JAK2-STAT1磷酸化級聯(lián)反應(yīng)，磷酸化STAT1入核后協(xié)同IRF家族蛋白，通過結(jié)合干擾素刺激反應(yīng)元件（ISRE）啟動數(shù)百種干擾素刺激基因（ISGs）轉(zhuǎn)錄，形成級聯(lián)放大效應(yīng)。

2、功能或作用機制

1）受體激活與激酶級聯(lián)

IFN-γ以同源二聚體形式結(jié)合異源二聚體受體IFNGR，誘導(dǎo)受體構(gòu)象變化。此過程激活受體偶聯(lián)的JAK1（結(jié)合IFNGR2）和JAK2（結(jié)合IFNGR1）酪氨酸激酶，觸發(fā)二者相互磷酸化。活化的JAK1進(jìn)一步磷酸化IFNGR1鏈第440位酪氨酸殘基（Y440），形成兩個相鄰的STAT1蛋白SH2結(jié)構(gòu)域結(jié)合位點^[12-14]。

2）STAT1磷酸化與復(fù)合物組裝

募集至受體的STAT1分子在其C端Y701位點被JAK激酶磷酸化，激活誘導(dǎo)STAT1同源二聚化并從受體解離，同源二聚體進(jìn)一步激活激活I(lǐng)RF-1（Interferon Regulatory Factor-1，干擾素調(diào)節(jié)因子-1）及IFN-γ激活序列（GAS），以啟動后續(xù)的基因轉(zhuǎn)錄調(diào)控，而少部分受體解離的STAT1會與STAT2及IRF-9形成異源復(fù)合物^[15-17]。其中，STAT1:STAT1:IRF-9復(fù)合物調(diào)控經(jīng)典GAS（IFN-γ-激活序列）響應(yīng)基因；STAT1:STAT2:IRF-9（ISGF3復(fù)合物）：靶向ISRE（干擾素刺激反應(yīng)元件）

3）核轉(zhuǎn)位與基因轉(zhuǎn)錄調(diào)控

磷酸化Stat1同源二聚體與ISGF3復(fù)合物轉(zhuǎn)位入核，分別結(jié)合靶基因啟動子區(qū)的GAS和ISRE元件^[18]。IRF-1作為次級轉(zhuǎn)錄因子，進(jìn)一步擴大調(diào)控網(wǎng)絡(luò)。此過程激活包括ICAM-1（細(xì)胞間黏附分子）、iNOS（誘導(dǎo)型一氧化氮合酶）及IRF家族成員在內(nèi)的多種干擾素調(diào)控基因，形成多層級轉(zhuǎn)錄放大效應(yīng)。

3、臨床應(yīng)用

1）抗感染

IFN-γ作為一種重要的免疫調(diào)節(jié)因子，在抗感染過程中發(fā)揮著關(guān)鍵作用。它通過激活巨噬細(xì)胞，增強其吞噬和殺傷能力，促進(jìn)抗原提呈，從而提高機體對病原體的清除效率^[20]。此外，IFN-γ還能誘導(dǎo)產(chǎn)生抗菌肽和其他具有直接殺菌作用的分子，進(jìn)一步加強宿主防御功能。

2）抗腫瘤

IFN-γ在腫瘤免疫監(jiān)視中占據(jù)核心地位，能夠直接抑制腫瘤細(xì)胞增殖，并通過多種途徑增強機體的抗腫瘤免疫反應(yīng)。IFN-γ可以上調(diào)MHC I類分子表達(dá)，使腫瘤細(xì)胞更容易被識別；刺激NK細(xì)胞、T細(xì)胞等效應(yīng)細(xì)胞的活性；誘導(dǎo)免疫檢查點分子如PD-L1的表達(dá)，進(jìn)而調(diào)節(jié)腫瘤微環(huán)境中的免疫平衡^[11,21-22]。

3）自身免疫性疾病

過度活躍的IFN-γ信號可能導(dǎo)致自身免疫性疾病的發(fā)生和發(fā)展，如系統(tǒng)性紅斑狼瘡（SLE）、多發(fā)性硬化癥（MS）等^[23-24]。針對IFN-γ信號通路的關(guān)鍵節(jié)點進(jìn)行干預(yù)，如使用單克隆抗體阻斷IFN-γ與其受體結(jié)合，或設(shè)計小分子化合物抑制下游信號傳導(dǎo)，可有效控制病情進(jìn)展，減少并發(fā)癥。

4）移植排斥反應(yīng)

術(shù)后，供體與受體之間的HLA（Human Leukocyte Antigen，人類白細(xì)胞抗原）差異是引發(fā)急性排斥反應(yīng)的主要原因。IFN-γ在此過程中扮演重要角色，它能增強移植物特異性T細(xì)胞的活化，加劇局部炎癥反應(yīng)，最終導(dǎo)致移植物功能喪失。IFN-γ抑制藥物可下調(diào)移植排斥介導(dǎo)的免疫應(yīng)答。此外，IL-10等具有抗炎效果的細(xì)胞因子，可以作為潛在的治療策略，減輕IFN-γ帶來的不利影響^[25]。

5）神經(jīng)退行性疾病

IFN-γ在神經(jīng)退行性疾病如阿爾茨海默病（AD）、帕金森病（PD）中顯示出復(fù)雜的雙重作用。一方面，適度的IFN-γ水平有助于清除β-淀粉樣蛋白沉積物，減緩疾病進(jìn)程；另一方面，過量的IFN-γ可能會加重神經(jīng)炎癥，損害神經(jīng)元結(jié)構(gòu)與功能^[26]。針對IFN-γ在神經(jīng)退行性疾病中的復(fù)雜角色，未來的研究需要更加細(xì)致地解析其調(diào)控網(wǎng)絡(luò)，以期找到既能利用其有益效應(yīng)又能避免不良后果的治療方案。

相關(guān)產(chǎn)品

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