Th22細(xì)胞因子協(xié)同促進(jìn)小鼠輸卵管上皮細(xì)胞抗沙眼衣原體感染體外研究

徐玲娟，趙秀敏，朱丹陽(yáng)，許 文

Th22細(xì)胞因子協(xié)同促進(jìn)小鼠輸卵管上皮細(xì)胞抗沙眼衣原體感染體外研究

徐玲娟1，趙秀敏2，朱丹陽(yáng)2，許 文3

目的 體外研究Th22細(xì)胞因子(IL-22、TNF-α)在小鼠輸卵管上皮細(xì)胞抵抗沙眼衣原體感染過(guò)程中的作用。方法 體外培養(yǎng)Th22細(xì)胞，ELISA檢測(cè)Th22上清中細(xì)胞因子含量及其對(duì)體外培養(yǎng)的小鼠輸卵管上皮細(xì)胞(MOECs)表達(dá)Th1趨化因子、抗菌肽的影響；Transwell實(shí)驗(yàn)檢測(cè)MOECs上清對(duì)Th1細(xì)胞的趨化能力；分別用免疫熒光法、PCR及7-乙氧基試鹵靈(7-ethoxyresrufin, 7-ER)法檢測(cè)Th22上清對(duì)輸卵管上皮細(xì)胞抑制Chlamydiatrichomatis(Ct)能力、促進(jìn)胰島再生源蛋白3g(regenerating islet-derived protein-3g,Reg3g)Reg3g表達(dá)及細(xì)胞活性的影響。結(jié)果 Th22細(xì)胞以分泌IL-22、TNF-α為主。Th22上清可誘導(dǎo)MOECs表達(dá)Th1細(xì)胞趨化因子CXCL9/10/11及抗菌肽mBD-2表達(dá)，活化MOECs對(duì)Th1細(xì)胞具有趨化作用并抑制Ct生長(zhǎng)。同時(shí)，Th22上清可促進(jìn)MOECsReg3g表達(dá)及增強(qiáng)其活性。結(jié)論 Th22細(xì)胞因子能增強(qiáng)MOECs介導(dǎo)的天然免疫功能，促進(jìn)其損傷修復(fù)，在Ct及其它性傳播疾病中可能發(fā)揮重要作用。

細(xì)胞因子；IL-22；TNF-α；小鼠輸卵管上皮細(xì)胞；Th22細(xì)胞

Th22細(xì)胞是一類(lèi)新發(fā)現(xiàn)的輔助性T細(xì)胞，以膜表面表達(dá)CCR10及分泌IL-22、TNF-α為主要特征，在監(jiān)督和協(xié)調(diào)引起炎癥的免疫細(xì)胞過(guò)程中發(fā)揮作用[1-2]。研究表明，IL-22可單獨(dú)或協(xié)同IL-17或TNF-α誘導(dǎo)上皮細(xì)胞產(chǎn)生抗微生物肽及多種趨化因子，在皮膚黏膜損傷修復(fù)及抗微生物感染中發(fā)揮重要作用[3-4]。以IL-22還可做為分子佐劑，可有效增強(qiáng)DNA疫苗誘導(dǎo)的Th1免疫反應(yīng)。在慢性以及過(guò)敏性炎癥疾病，如牛皮癬、過(guò)敏性濕疹等疾病中; Th22細(xì)胞功能的喪失將使慢性炎癥疾病惡化。因此，Th22細(xì)胞可能是治療慢性炎癥疾病的潛在靶標(biāo)。在Ct、陰道毛滴蟲(chóng)等性傳播病原體感染的患者陰道分泌物中IL-22明顯升高[5]，因此,我們推測(cè)Th22細(xì)胞及其細(xì)胞因子在生殖道黏膜免疫中亦發(fā)揮重要作用。本實(shí)驗(yàn)應(yīng)用體外培養(yǎng)小鼠輸卵管上皮細(xì)胞模型, 分析兩種關(guān)鍵Th22細(xì)胞因子IL-22、TNF-α對(duì)小鼠輸卵管上皮細(xì)胞免疫功能的影響, 為時(shí)一步探討Th22細(xì)胞及其細(xì)胞因子在生殖道黏膜免疫中的作用。

1 材料與方法

1.1 鼠 雌性6～8周齡的BALB/c小鼠購(gòu)自中科院上海實(shí)驗(yàn)動(dòng)物中心。

1.2 主要試劑 HeLa 229 cells及CtE型株購(gòu)自ATCC?？股逞垡略wLPS多克隆抗體購(gòu)自Abcam?？故驣L-22、TNF-α抗體及鼠IgG1同型對(duì)照抗體(BD 公司，美國(guó))?？故驝D3、CD28, IFN-γ、IL-4 單抗及重組鼠TNF-α, IL-6, and IL-2;CXCL-9, -10, 及-11 ELISA kits 均購(gòu)自 R&D公司。mBD-2試劑盒購(gòu)自Phoenix Pharmaceuticals公司。FITC標(biāo)記抗鼠CD4單抗、PE標(biāo)記抗鼠CXCR3單抗購(gòu)自Pharmingen。7-乙氧基試鹵靈(7-ethoxyresrufin , 7 -ER )購(gòu)自Sigma公司。

1.3 Th22細(xì)胞誘導(dǎo)及小鼠輸卵管上皮細(xì)胞的原代培養(yǎng) 磁珠分離BALB/c小鼠脾CCR10+CD4+T細(xì)胞，以1 μg/mL抗CD3、2 μg/mL抗CD28、5 μg/mL IFN-γ、5 μg/mL IL-4 單抗及細(xì)胞因子50 ng/IL-6、20 ng/mL TNF-α100 U/mL IL-2 (Th22 條件)刺激[3]，誘導(dǎo)Th22細(xì)胞極化，流式分析表型(BD FACS Calibur)。于第7 d，以抗CD3、抗CD28抗體刺激，收集上清，-80 ℃凍存。

MOECs的原代培養(yǎng)參見(jiàn)文獻(xiàn)[6]。1×105MOECs/孔，接種接種于24孔板中，加入培養(yǎng)基2 mL, 細(xì)胞貼壁生長(zhǎng)至85% 時(shí)，準(zhǔn)備Th22上清干預(yù)。干預(yù)前基礎(chǔ)培養(yǎng)基饑餓培養(yǎng)細(xì)胞過(guò)夜， 次日上午于各培養(yǎng)皿中分別加入Th22上清，分別于24、48、72 h 后分離上清，-80 ℃凍存。

1.4 ELISA檢測(cè)細(xì)胞因子 依說(shuō)明書(shū)操作，檢測(cè)Th22上清中IL-22, TNF-α, IL-17, IFN-γ、IL-4 含量及 MOECs上清中mBD-2 and CXCL-9, -10及-11含量。

1.5 Transwell遷移實(shí)驗(yàn) 磁珠分離BALB/c 小鼠脾細(xì)胞中CD4+T 細(xì)胞，抗CD3 (1 μg/mL), 抗CD28 (2 μg/mL), 5 μg/mL 抗鼠IL-4及25 ng/mL IL-12 (Th1 條件) 刺激48 h后，離心、移除上清，補(bǔ)新鮮完全RPMI-1640，繼續(xù)培養(yǎng)48 h，以誘導(dǎo)CXCR3表達(dá)。2×105CD4+T細(xì)胞加于Transwell上室，下室加MOECs培養(yǎng)上清。37 ℃，5% CO2培養(yǎng)4 h 后置于 4 ℃ 20 min以分離膜上細(xì)胞，流式分析遷移的CD4+T數(shù)及其CXCR3表達(dá)。

遷移阻斷實(shí)驗(yàn)：抗CXCR3 抗體(5 μg/ml)或同型對(duì)照抗體預(yù)先與激活的淋巴細(xì)胞在37 ℃孵育30 min， 然后用所收集的細(xì)胞上清液做遷移實(shí)驗(yàn)。實(shí)驗(yàn)重復(fù)3 次。

1.6 免疫熒光檢測(cè)活化MOECs抑制Ct增殖能力 3×104MOECs/孔置于96孔板中，1.2×103CtEB與100 μL MOECs培養(yǎng)上清(見(jiàn)上述)于37 ℃孵育45 min后加入上述孔中，室溫250×g離心40 min，棄上清，補(bǔ)200 μL完全1640(含10%胎牛血清)。37 ℃，5% CO2繼續(xù)培養(yǎng)40 h，10% 甲醇固定10 min, 加入兔抗Ct特異性脂多糖抗體200 μL, 37 ℃ 1 h, PBS洗滌后加入羊抗兔IgG-FITC 200 μL 30 min, PBS洗滌后甘油封片，熒光顯微鏡下(40×)計(jì)數(shù)檢測(cè)包涵體。

1.7 PCR檢測(cè)Reg3β表達(dá)Ct感染MOECs 24 h、48 h后，RT-PCR檢測(cè)再生蛋白(regenerating protein 3β,Reg3β) mRNA表達(dá)，引物序列為 5′-CGCATTAGTTGCCCCAAGG-3′ and 5′-TCCAGGCCTCTTTTGGCAG-3′. 提取Th22上清處理的MOECs總RNA，合成 cDNA。

1.8 細(xì)胞活性檢測(cè)Ct感染MOECs 24 h、48 h后，依說(shuō)明書(shū)操作，熒光分光光度計(jì)檢測(cè)試鹵靈吸光度。

2 結(jié) 果

2.1 Th22細(xì)胞誘導(dǎo) Th22 細(xì)胞是新發(fā)現(xiàn)的CD4+T 細(xì)胞，以膜表達(dá)CCR10及分泌IL-22為特征。因此，在本研究中采用抗CD3、CD28、IFN-γ、IL-4單抗及細(xì)胞因子IL-6、TNF-α 、IL-2組合刺激BALB/c小鼠來(lái)源的CCR10+CD4+T細(xì)胞誘導(dǎo)Th22細(xì)胞極化。7 d后，以抗CD3、CD28刺激活化后，流式分析表明所得CD4+T 細(xì)胞表達(dá)Th22標(biāo)志CCR10 及IL-22 及 TNF-α(圖1). ELISA分析上清進(jìn)一步表明，所得T細(xì)胞高表達(dá)Th22特征細(xì)胞因子IL-22、TNF-α而低表達(dá)Th1、Th2、Th17細(xì)胞因子IFN-γ、IL-4及IL-17(表1)。

By flow cytometry, freshly isolated CCR10+CD4+T cells from the spleens of normal mice (left panel) and polarized Th22-type cells (right panel) were stained with anti-CCR10, anti-CD4, anti-IL-22, and anti-TNF-α Abs after permeabilization. The percentage of cells that were double-positive for CCR10 and CD4 (A and B) or IL-22 and TNF-α are shown (C and D).

圖1 Th22細(xì)胞誘導(dǎo)

Fig.1 Polarization of CD4+T cells into IL-22- and TNF-α-producing cells

表1 Th22細(xì)胞因子檢測(cè)

Note: We set up Th22-type cells from spleens of BALB/c mice. Supernatants were measured 48 hrs after anti-CD3/CD28 stimulation.

2.2 Th22上清誘導(dǎo)MOECs產(chǎn)生Th1趨化因子CXCL9/10/11及抗菌肽mBD-2 為檢測(cè)Th22上清能否刺激MOECs天然免疫功能，MOECs經(jīng)Th22上清作用24、48及72 h后，收集培養(yǎng)上清，ELISA檢測(cè)CXCL9、CXCL10、CXCL11及mBD-2濃度。如圖2所示，Th22上清能夠誘導(dǎo)小鼠輸卵管上皮細(xì)胞產(chǎn)生CXCL9、CXCL10、CXCL11及mBD-2， anti-IL-22/TNF-α抗體顯著抑制Th22上清的刺激作用，排除了其它細(xì)胞因子干擾的可能。

MOECs were stimulated with medium alone, IL-22, TNF-α, IL-22+TNF-α, or Th22 cell supernatant for 24, 48, or 72 hrs. For neutralization experiments, Th22 cell supernatants were pretreated with anti-IL-22+TNF-α mAbs for 30 min and then were used to stimulate MOECs. The levels of (A) CXCL-9, (B) CXCL-10, (C) CXCL-11, and (D) mBD-2 over a time-course in cell-free supernatants were quantified using ELISA kits. *P<0.05, **P<0.01, compared with the untreated control group; #P<0.05, ##P<0.01, compared with corresponding Th22 supernatant untreated by anti-IL-22/TNF-α mAbs.

圖2 ELISA檢測(cè)Th22上清刺激MOECs表達(dá)Th1趨化因子CXCL9/10/11及抗菌肽mBD-2表達(dá)

Fig.2 MOECs producing Th1 cell-associated chemokines and mBD-2 after IL-22+TNF-α stimulation

2.3 活化MOECs具有趨化Th1細(xì)胞的作用 T細(xì)胞介導(dǎo)的細(xì)胞免疫在清除Ct等性傳播病原中發(fā)揮關(guān)鍵作用。CXCL9、CXCL10、CXCL11可與效應(yīng)T細(xì)胞表面CXCR3受體結(jié)合募集T細(xì)胞進(jìn)入炎癥部位。本研究中我們通過(guò)Transweell實(shí)驗(yàn)觀察Th22上清活化的MOECs趨化CXCR3+T細(xì)胞的能力。結(jié)果顯示活化的MOECs具有趨化活化T細(xì)胞的能力，與未刺激對(duì)照組比較差異有統(tǒng)計(jì)學(xué)意義?？筧nti-IL-22及TNF-α抗體顯著抑制Th22上清誘導(dǎo)的趨化作用。

2.4 Th22細(xì)胞因子具有促進(jìn)MOECs損傷修復(fù)的作用 由于IL-22 在上皮細(xì)胞的損傷修復(fù)中扮演重要作用，在本研究中，我們以體外感染Ct的MOECs為模型，進(jìn)一步檢測(cè)了Th22上清對(duì)生殖道上皮細(xì)胞的保護(hù)作用。首先，我們檢測(cè)了Th22上清活化的MOECs能否抑制Ct生長(zhǎng)。結(jié)果表明，以Th22上清活化的MOECs具有抑制生長(zhǎng)的能力，與未處理對(duì)照組比較具有顯著差異。以anti-IL-22及TNF-α抗體封閉的Th22上清處理的MOECs抑制Ct生長(zhǎng)的能力顯著下降。 接著，我們檢測(cè)了Th22

MOECs were stimulated by Th22 supernatant for 48 hrs. Then, supernatants were collected and analyzed by chemotaxis assay to assess the chemotactic activity of supernatants for Th1 cells. **P<0.01, compared with control; #P<0.05, compared with corresponding T cells that were not treated with CXCR3 antibody.

圖3 Th22上清活化的MOECs誘導(dǎo)Th1細(xì)胞遷移

Fig.3 Migration of Th1 cells induced by supernatants of MOECs treated with Th22 cell supernatant

上清對(duì)MOECs表達(dá)Reg3β的影響。Reg3β是促進(jìn)上皮組織損傷修復(fù)的一個(gè)重要蛋白。結(jié)果表明，Th22上清具有促進(jìn)Reg3β表達(dá)的作用。另外，我們的結(jié)果還證明了Th22上清具有促進(jìn)MOECs活性的作用。以上結(jié)果表明，Th22細(xì)胞因子具有促進(jìn)MOECs損傷修復(fù)的作用。

(A) MOEC supernatants from Th22 cell supernatant stimulation significantly inhibitedCtgrowth. Data are expressed relative values compared with the IFU/well resulting from infection with untreatedCt; (B) 24 and 48 h later, cell viability was quantified using Resorufin; (C)REG3βmRNA copy numbers were measured by quantitative RT-PCR.

Data are normalized to the expression ofβ-actin, and are expressed as the fold-increase over the average gene expression in untreated MOECs.

*P<0.05, **P<0.01, compared with the control group; #P<0.05, ##P<0.01, compared with the corresponding Th22 cell supernatant untreated by anti-IL-22 or TNF-α mAbs group.

圖4 IL-22 and TNF-α 協(xié)同促進(jìn)MOECs損傷修復(fù)

Fig.4 IL-22 and TNF-α co-operate to protect MOECs againstCt

3 討 論

Th22細(xì)胞主要通過(guò)協(xié)調(diào)其它炎癥細(xì)胞從而在慢性炎癥疾病中發(fā)揮重要作用。IL-22、TNF-α是兩個(gè)關(guān)鍵的Th22細(xì)胞因子。IL-22受體由IL-22R1與IL-10R2組成。 由于IL-22R1主要表達(dá)于皮膚黏膜細(xì)胞并決定細(xì)胞對(duì)IL-22的反應(yīng)性，故上皮細(xì)胞等組織細(xì)胞為IL-22的主要靶細(xì)胞[7]。IL-22可單獨(dú)或協(xié)同TNF-α還可誘導(dǎo)上皮細(xì)胞表達(dá)抗菌肽(如防御素、S100A7等)及Th1趨化因子CXCL9 /10/11的表達(dá)，具有抑制細(xì)菌生長(zhǎng)及募集效應(yīng)T細(xì)胞進(jìn)入炎癥部位的作用[4, 8]。IL-22還可促進(jìn)上皮細(xì)胞損傷修復(fù)[4]。

包括我們前期研究在內(nèi)的結(jié)果表明Ct等性傳播病原體感染患者陰道分泌物中IL-22水平明顯上升且輸卵管上皮細(xì)胞可表達(dá)IL-22特異受體IL-22R1[9]，因此我們推測(cè)Th22細(xì)胞及其細(xì)胞因子在生殖道黏膜免疫中亦發(fā)揮重要作用。由于mBD-2及CXCL9/10/11具有抗菌及趨化Th1細(xì)胞的作用，因此，在本研究中，我們建立了Th22細(xì)胞系并觀察其培養(yǎng)上清對(duì)MOECs產(chǎn)生mBD-2及CXCL9/10/11的影響。結(jié)果表明，Th22細(xì)胞上清能有效誘導(dǎo)MOECs產(chǎn)生mBD-2及趨化因子CXCL9/10/11。中和IL-22、TNF-α可有效抑制抗菌肽及趨化因子的表達(dá)，因而排除了其它細(xì)胞因子干擾的可能。

女性生殖道是HIV、HPV、HSV-2及Ct等性傳播病原體的入口[10]。T細(xì)胞介導(dǎo)的細(xì)胞免疫在清除這些性傳播病原體的過(guò)程中發(fā)揮重要作用。然而由于特殊的解剖屏障，T細(xì)胞難于進(jìn)入生殖道。而趨化因子CXCL9/1011可與效應(yīng)T細(xì)胞及記憶T細(xì)胞上CXCR3受體結(jié)合促進(jìn)其進(jìn)入生殖道發(fā)揮效應(yīng)作用[11]。有證據(jù)表明，沙眼衣原體感染小鼠輸卵管組織中CXCL9、CXCL10 CXCL11表達(dá)明顯升高，且與沙眼衣原體的清除有關(guān)[12]。本研究中，通過(guò)Transwell實(shí)驗(yàn)，我們亦證實(shí)了Th22活化的MOECs具有趨化CXCR3+T細(xì)胞的作用。另外，Th22活化的MOECs培養(yǎng)上清可顯著抑制Ct的生長(zhǎng)。這些結(jié)果表明，Th22細(xì)胞因子具有調(diào)節(jié)MOECs免疫功能的效應(yīng)。

Reg3g蛋白家族屬于C-類(lèi)凝集素家族,具有抗菌、促進(jìn)細(xì)胞增殖、抑制炎癥和細(xì)胞凋亡的作用[13-14]。IL-22可活化STAT3信號(hào)途徑，進(jìn)而調(diào)節(jié)Reg3g蛋白的表達(dá)，促進(jìn)上皮細(xì)胞損傷修復(fù)。我們前期的研究表明，IL-22可上調(diào)MOECs STAT3表達(dá)，因此在本研究中我們進(jìn)一步觀察了Th22細(xì)胞因子對(duì)MOECs表達(dá)Reg3g的影響。結(jié)果顯示，IL-22、TNF-α可協(xié)同促進(jìn)Reg3g的表達(dá)并增加MOECs的活性。這表明，Th22細(xì)胞因子具有促進(jìn)MOECs損傷修復(fù)的作用。

綜上所述，本研究認(rèn)為，Th22細(xì)胞因子具有調(diào)節(jié)MOECs免疫功能并促進(jìn)其損傷修復(fù)的作用，這為進(jìn)一步研究Th22細(xì)胞及其細(xì)胞因子在生殖道黏膜免疫中的作用提供了實(shí)驗(yàn)依據(jù)。

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[3]Sugita S, Kawazoe Y, Imai A, et al. Role of IL-22- and TNF-alpha-producing Th22 cells in uveitis patients with Behcet’s disease[J]. J Immunol, 2013, 190(11): 5799-5808.

[4]Eyerich S, Wagener J, Wenzel V, et al. IL-22 and TNF-alpha represent a key cytokine combination for epidermal integrity during infection withCandidaalbicans[J]. Eur J Immunol, 2011, 41(7): 1894-1901.

[5]Makinde HM, Zariffard R, Mirmonsef P, et al. IL-22 levels are associated withTrichomonasvaginalisinfection in the lower genital tract[J]. Am J Reprod Immunol, 2013, 70(1): 38-44.

[6]Li X，Xu W. The expression of murin β-defensin-2 in murine oviduct epithelial cells induced by IL-22[J]. Prog Obstet Gynecol，2014, 23(08): 627-629.

[7]Pham TA, Clare S, Goulding D, et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen[J]. Cell Host Microbe, 2014, 16(4): 504-516.

[8]Guilloteau K, Paris I, Pedretti N, et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1{alpha}, and TNF-{alpha} recapitulates some features of psoriasis[J]. J Immunol, 2010, 184(9): 5263-5270.

[9]Frazer LC, Scurlock AM, Zurenski MA, et al. IL-23 induces IL-22 and IL-17 production in response toChlamydiamuridarumgenital tract infection, but the absence of these cytokines does not influence disease pathogenesis[J]. Am J Reprod Immunol, 2013, 70(6): 472-484.

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Potential protective role of the Th22 cytokines againstChlamydiatrichomatisinfection in genital tract

XU Ling-juan1,ZHAO Xiu-min2,ZHU Dan-yang2,XU Wen3

(1.DepartmentofLaboratoryMedicine,HospitalofTraditionalChineseMedicineofJinhuaCity,Zhejiang318300,China;2.DepartmentofObstetricsandGynecology,TaizhouFirstPeople’sHospital,Taizhou318020,China;3.DepartmentofMicrobiologyandImmunology,WengzhouMedicalUniversity,Wengzhou325035,China)

Th22 cells are a novel class of leukocytes characterized by the secretion of both IL-22 and TNF-α. Th22 cells have little or no direct impact on other immune cells, but exert selective effects on epithelia. It is not known, however, whether Th22 cells play a role in genital mucosal immunity. Here, we demonstrate that IL-22 and TNF-α synergistically induce several immunomodulatory molecules, such as the antimicrobial peptide mBD-2 (murine β-defensin 2) and the antimicrobial chemokines CXCL-9, -10, and -11 in primary murine oviduct epithelial cells (MOECs). The induction of innate immunity is relevant in aninvitroinfection model, in which MOECs stimulated with Th22 cell supernatants effectively inhibit the growth ofChlamydiatrichomatisand maintain the survival of the epithelia compared with untreated control. In summary, we demonstrate that the Th22 cell cytokines IL-22 and TNF-α play important roles in genital tract infection. The potential for Th22 cell cytokines to modulate innate immune mediators may lead to the development of new topical agents to treat and/or prevent immune-mediated STDs.

IL-22; defensin; chemokine; oviduct epithelial cell; Th22 cell

10.3969/cjz.j.issn.1002-2694.2015.08.012

許文，Email：wenxu.cn@gmail.com

1.浙江金華市中醫(yī)院檢驗(yàn)科，金華 321017； 2.浙江臺(tái)州第一人民醫(yī)院婦產(chǎn)科，臺(tái)州 318300； 3.溫州醫(yī)科大學(xué)微生物學(xué)與免疫學(xué)教研室，溫州 325035

Correponding author: Xu Wen, Email: wenxu.cn@gmail.com

R374

A

1002-2694(2015)08-0742-05

2014-10-30；

2015-03-26

浙江省自然科學(xué)基金((Y2 110670)；溫州市科技局項(xiàng)目(Y20110126)聯(lián)合資助

Supported by the Zhejiang Provincial Natural Science Foundation (No. Y2 110670) and the Science and Technology Planning Project of Wenzhou Municipal (No. Y20110126)