摘要
目的：IL-23／Th17细胞轴在许多炎症性疾病中发挥着重要的调节作用,但IL-23在过敏性气道炎症中的作用尚不十分清楚。本文旨在观察IL-23-IL-23R信号是否参与了哮喘过敏性气道炎症的发生,并进一步探讨其调控过敏性气道炎症的可能机制。
方法：(1)选取卵清蛋白(OVA)致敏和非致敏的B6背景雌性小鼠各4-6只,提取其肺组织,采用RT-PCR法测定IL-23p19, IL-12p35, IL-12/IL-23p40和IL-23受体(IL-23R)mRNA的表达。(2)选取IL-23基因敲除(IL-23 KO)及相同背景的野生型雌性小鼠各4-6只,OVA致敏诱导哮喘模型。提取肺组织,采用HE染色了解炎症细胞在肺部的浸润情况。进行肺泡灌洗,计数肺泡灌洗液中的细胞总数,以及采用细胞甩片及Giemsa染色技术,进行细胞分类的计数。RT-PCR法测定肺组织中嗜酸性粒细胞过氧化物(EPO)的表达。ELISA法测定血清中OVA特异性IgE的表达及肺引流淋巴结细胞和脾细胞体外经OVA再刺激后,Th2和Th17相关细胞因子的水平。(3)利用人类CD2位点启动子,产生在T细胞上过度表达IL-23R的两组转基因小鼠。RT-PCR法测定其IL-23R的表达水平,选取其中一组作为实验用小鼠。选取IL-23R转基因(IL-23R Tg)和B6小鼠,分别从其脾及浅表淋巴结组织中通过流式分选出原始T淋巴细胞(naive T细胞)。经过Th17及Thl条件下的体外活化4天,在伴或不伴重组鼠细胞因子IL-23的作用下,流式细胞术测定产生IL-17及IFN-γ的细胞比例。(4)选取IL-23RTg及相应的野生型B6雌性小鼠各4-6只,OVA致敏诱导哮喘模型。提取肺组织,采用HE染色了解炎症细胞在肺部的浸润情况。进行肺泡灌洗,计数肺泡灌洗液中的细胞总数,以及采用细胞甩片及Giemsa染色技术,进行细胞分类的计数。RT-PCR法测定肺组织中EPO的表达。ELISA法测定血清中OVA特异性IgE的表达及肺引流淋巴结细胞和脾细胞体外经OVA再刺激后,Th2和Th17相关细胞因子的水平。(5)选取IL-23 KO及相应的野生型小鼠,采用流式细胞术从野生型小鼠的脾及浅表淋巴结组织中分选出原始T淋巴细胞,从IL-23 KO及野生型小鼠的脾组织中分别分选出经放射线处理后的抗原呈递细胞(APC)。在IL-2,IL-4及抗IFN-γ(anti-IFN-γ)细胞因子的存在下,naive T细胞经抗CD3 (anti-CD3)及分别来自IL-23 KO及野生型小鼠的APC的重新刺激。5天后,流式细胞术测定产生IL-4及IL-17的细胞比例。ELISA法测定Th2相关细胞因子的水平。RT-PCR法测定转录因子T-bet,GATA-3和Foxp3的表达。(6)选取IL-23R Tg及相应的野生型小鼠,分别从其脾及浅表淋巴结组织中通过流式分选出原始T淋巴细胞。在IL-2,IL-4及anti-IFN-γ,伴或不伴重组鼠细胞因子工L-23的存在下,naiveT细胞分别经anti-CD3及anti-CD28的重新刺激。5天后,流式细胞术测定产生IL-4及IL-17的细胞比例。ELISA法测定Th2相关细胞因子的水平。RT-PCR法测定转录因子T-bet, GATA-3和Foxp3的表达。
结果：(1)OVA致敏小鼠的肺部IL-23p19, IL-12p35, IL-12/IL-23p40和IL-23RmRNA的表达均较未致敏小鼠显著升高(P<0.05)。(2)OVA致敏诱导的哮喘模型中,IL-23 KO小鼠肺部炎症细胞的浸润较野生型小鼠明显受到了抑制。IL-23KO小鼠肺泡灌洗液中细胞总数较野生型小鼠显著降低(P<0.05),其中单核巨嗜细胞、中性粒细胞和嗜酸性粒细胞的数量均显著减少(P<0.05),淋巴细胞轻度减少(P>0.05)。IL-23 KO小鼠肺部EPO的表达及血清中IgE的水平均较野生型小鼠显著降低(P<0.05)。IL-23 KO小鼠肺引流淋巴结细胞及脾细胞体外OVA再刺激后,肺引流淋巴结细胞IL-5及IL-13的分泌水平较野生型小鼠显著降低(P<0.05),IL-4轻度降低(P>0.05),脾细胞IL-4,IL-5和IL-13的分泌水平均较野生型小鼠显著降低(P<0.05)。而肺引流淋巴结细胞及脾细胞分泌IL-17及IL-17F的水平未见明显差别。(3)所产生的IL-23R Tg小鼠胸腺IL-23R的表达水平较野生型小鼠显著升高,选取其中一组进行实验。在Th17条件下,IL-23R Tg小鼠的T细胞分化较野生型小鼠,加入重组鼠细胞因子IL-23极大地提高了产生IL-17细胞的比例；在Thl条件下,IL-23R Tg小鼠的T细胞分化较野生型小鼠,加入重组鼠细胞因子IL-23显著抑制了产生IFN-γ细胞的比例。(4)OVA致敏诱导的哮喘模型中,IL-23RTg小鼠肺部炎症细胞的浸润较野生型小鼠明显增加。IL-23RTg小鼠肺泡灌洗液中细胞总数较野生型小鼠显著升高(P<0.05),其中单核巨嗜细胞、中性粒细胞和嗜酸性粒细胞的数量均显著增加(P<0.05),淋巴细胞轻度增加(P>0.05)。IL-23RTg小鼠肺部EPO的表达及血清中IgE的水平均较野生型小鼠显著升高(P<0.05)。IL-23R Tg小鼠肺引流淋巴结细胞及脾细胞体外OVA再刺激后,肺引流淋巴结细胞及脾细胞分泌IL-4,IL-5和IL-13的水平均较野生型小鼠显著增高(P<0.05),而其分泌IL-17及IL-17F的水平未见明显差别。(5)原始T淋巴细胞在IL-23缺陷的APC活化下,产生IL-4细胞的比例较野生型APC明显减少,其分泌的细胞因子IL-4及IL-5显著降低(P<0.05),IL-13轻度降低(P>0.05),同时转录因子GATA3的表达明显降低(P<0.05), T-bet及Foxp3的表达轻度升高(P>0.05)。(6)来自IL-23R Tg小鼠的原始T淋巴细胞在anti-CD3及anti-CD28的刺激下,增加重组鼠细胞因子IL-23使产生IL-4的细胞比例明显增加,其分泌的细胞因子IL-4及IL-13显著增加(P<0.05),IL-5轻度增加(P>0.05)。来自野生型小鼠的原始T淋巴细胞在重组鼠细胞因子IL-23的作用下,仅IL-13的分泌显著增加(P<0.05)。同时,在IL-23的刺激下,仅IL-23R Tg小鼠T细胞引起转录因子GATA3的表达显著增加(P<0.05)。
结论：IL-23-IL-23R信号参与了哮喘过敏性气道炎症的发生,它不仅可以通过维持IL-17的产生来形成嗜中性粒细胞炎症,更重要的是可能通过直接调节Th2细胞的分化来影响过敏性气道炎症。
Objective:IL-23/Th17 axis is an important regulator in various inflammatory diseases. However, the role of IL-23 in allergic airway inflammation is not well understood. This study aims to observe whether IL-23-IL-23R signaling is involved in the development of allergic airway inflammation, furthermore, to investigate the possible mechanisms.
Methods:(1) mRNA expression of IL-23p19, IL-12p35, IL-12/IL-23p40 and IL-23R was determined by real-time PCR in whole lung tissue from OVA-challenged B6 female mice. Non-challenged B6 female mice were used as control. (2) IL-23 KO and WT female mice were subjected to OVA-sensitizing-induced asthma. Inflammatory infiltrates in lung were assessed by HE staining. Total cells of bronchoalveolar lavage fluid (BALF) from the asthmatic mice were counted. Cellular profiles in BALF upon OVA challenge were assessed by cytospin with May-Gruenwald Giemsa staining. EPO expression in lung was determined by real-time PCR. OVA-specific IgE expression in sera was measured by ELISA. Expression of type-2 cytokines in lung draining lymph node cells and splenocytes after ex vivo OVA restimulation was assessed by ELISA. OVA-specific Th17 cytokine expression was determined by ELISA. (3) Generation two lines of IL-23R Tg mice with IL-23R overexpression in T cells using the human CD2 mini locus promoter. IL-23R mRNA expression was tested by real-time PCR. One of the two lines was extensively analyzed. Naive T cells were FACS-sorted from IL-23R Tg or B6 mice and activated under Thl7 and Thl conditions with or without recombinant mouse IL-23. Four days later, IFN-y and IL-17-producing cells were analyzed by intracellular staining. (4) IL-23R Tg and B6 female mice were subjected to OVA-sensitizing-induced asthma. Inflammatory infiltrates in lung were assessed by HE staining. Total cells of bronchoalveolar lavage fluid (BALF) from the asthmatic mice were counted. Cellular profiles in BALF upon OVA challenge were assessed by cytospin with May-Gruenwald Giemsa staining. EPO expression in lung was determined by real-time PCR. OVA-specific IgE expression in sera was measured by ELISA. Expression of type-2 cytokines in lung draining lymph node cells and splenocytes after ex vivo OVA restimulation was assessed by ELISA. OVA-specific Th17 cytokine expression was determined by ELISA. (5) Naive T cells were FACS-sorted and stimulated with anti-CD3 and irradiated splenic APC from IL-23 KO or WT mice in the presence of IL-2, IL-4, and anti-IFN-y. Five days later, IL-4 and IL-17-producing cells were analyzed by intracellular staining. Cytokine production was measured by ELISA. T-bet, GATA-3, and Foxp3 mRNA expression was analyzed by RT-PCR. (6) Naive T cells were FACS-sorted from IL-23R Tg or B6 mice and stimulated with anti-CD3 and anti-CD28 in the presence of IL-2, IL-4, and anti-IFN-y with or without recombinant mouse IL-23. Five days later, IL-4 and IL-17-producing cells were analyzed by intracellular staining. Cytokine production was measured by ELISA. T-bet, GATA-3, and Foxp3 mRNA expression was analyzed by RT-PCR.
Results:(1) IL-23p19, IL-12p35, IL-12/IL-23p40 and IL-23R mRNA were highly induced in the lungs from OVA-challenged mice compared with those from non-immunized mice (P＜0.05). (2) In OVA-sensitizing-induced asthma model, antigen-induced inflammatory cell infiltration was greatly inhibited in the lungs from IL-23 KO mice compared with that from WT mice. Total cell number was significantly decreased in IL-23 KO mice (P＜0.05). Eosinophils, macrophages and neutrophils were significantly decreased in IL-23 KO mice (P<0.05), and lymphcytes were slightly decreased (P>0.05). IL-23 deficiency led to dramatically decreased expression of EPO in IL-23 KO mice (P＜0.05). OVA-specific IgE expression is significantly lower than that in WT mice (P＜0.05). Upon ex vivo OVA restimulation, the expression of IL-4, IL-5, and IL-13 in lung draining lymph node cells and splenocytes from OVA-challenged IL-23 KO mice was significantly lower in comparison with WT cells (P＜0.05). OVA specific Th17 responses were observed at similar low levels in both IL-23 KO and WT mice. (3) IL-23R expression in thymus was significantly higher in IL-23 R Tg mice than in WT mice, one of the two lines was extensively analyzed. Under the Thl7 condition, addition of recombinant mouse IL-23 significantly increased the frequency IL-17-producing cells in IL-23R Tg T cells. Under the Thl condition, addition of recombinant mouse IL-23 greatly inhibited the generation of IFN-y-producing cells in IL-23R Tg T cells. (4) In OVA-sensitizing-induced asthma model, antigen-induced inflammatory cell infiltration was greatly increased in the lungs from IL-23R Tg mice compared with that from WT mice. Total cell number was significantly increased in IL-23R Tg mice (P＜0.05). Eosinophils, macrophages and neutrophils were significantly increased in IL-23R Tg mice (P＜0.05), and lymphcytes were slightly increased (P>0.05). IL-23R overexpression led to dramatically increased expression of EPO in IL-23R Tg mice (P＜0.05). OVA-specific IgE expression is significantly higher than that in WT mice (P<0.05). Upon ex vivo OVA restimulation, the expression of IL-4, IL-5, and IL-13 in lung draining lymph node cells and splenocytes from OVA-challenged IL-23R Tg mice was significantly higher in comparison with WT cells (P＜0.05). OVA specific Th17 responses were observed at similar low levels in both IL-23R Tg and WT mice. (5) CD4+T cells activated with IL-23-deficient APCs exhibited reduced IL-4-producing cell numbers, and visually no IL-17-producing cells were observed. IL-23-deficient APCs led to significantly reduced amounts of IL-4 and IL-5 expression by effector T cells (P＜0.05). GATA-3 mRNA expression was significantly decreased in T cells treated with IL-23 KO APCs compared with those treated with WT APCs (P＜0.05). (6) Addition of recombinant mouse IL-23 increased IL-4-producing cell numbers and protein expression of IL-4 and IL-13 in IL-23R Tg cells (P＜0.05). In WT T cells, only IL-13 was significantly enhanced by IL-23 treatment (P＜0.05). In response to IL-23 stimulation, IL-23R Tg but not WT T cells highly expressed GATA-3 mRNA (P＜0.05).
Conclusion:IL-23-IL-23R signaling is involved in the development of allergic airway inflammation. IL-23 signaling may regulate allergic asthma through modulation of Th2 cell differenciation.
引文
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