慢性鼻—鼻竇炎伴息肉患者AhR表達與Th17反應相關性及AhR配體干預的研究
發(fā)布時間：2018-08-20 07:49
【摘要】：慢性鼻-鼻竇炎伴息肉(chronic rhinosinusitis with nasal polyps, CRSwNP)是耳鼻咽喉科臨床上常見的、多發(fā)的鼻腔和鼻竇粘膜的慢性炎癥性疾病。根據目前的流行病學調查顯示，CRSwNP在全球范圍內的發(fā)病率已高達2~5%，，其發(fā)生嚴重影響患者的生活和睡眠質量及工作效率，已成為人類主要的公共衛(wèi)生問題之一，同時也帶來了嚴重的經濟負擔。雖然CRSwNP目前的診療水平已經大幅度提高，但是其治療效果依然不能令所有患者滿意，且治療后復發(fā)率較高。在既往數(shù)十年，臨床耳鼻喉科醫(yī)生及科研工作者對CRSwNP的病因、發(fā)病機制和治療進行了深入而廣泛的探索和研究。目前認為，CRSwNP患者鼻腔和鼻竇粘膜的慢性炎癥主要是由諸如解剖結構異常、感染、變應性體質、免疫調節(jié)功能異常等單個或多個因素共同作用所致，其中Th17反應亢進導致的以Th17細胞過度活化及其相應的相關促炎細胞因子的大量釋放是造成國人CRSwNP發(fā)生發(fā)展的重要原因。 芳香烴受體(aryl hydrocarbon receptor, AhR)，一種依靠配體激活的轉錄因子，在調節(jié)人體免疫反應中發(fā)揮了重要作用。已有研究表明它參與了哮喘、特應性皮炎、實驗性自身免疫性腦脊髓炎和類風濕性關節(jié)炎等過敏性和自身免疫性疾病的發(fā)病機制。近期的動物實驗也顯示AhR可通過控制T淋巴細胞和樹突細胞（dendritic cells, DCs)的分化從而發(fā)揮強大的免疫調節(jié)能力。尤其值得注意的是，AhR一旦被它的天然配體諸如2-（1-吲哚-3-羰基）-噻唑-4-羧酸甲酯(2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester, ITE)激活，它就能抑制Th17反應，進而控制慢性炎癥。因此，我們假設AhR可能參與了CRSwNP患者慢性炎癥的形成。 本實驗的目的是探索AhR在伴變應性體質和不伴變應性體質的CRSwNP患者發(fā)病中的作用及其與CRSwNP患者Th17反應的相關性，并予以ITE體外干預CRSwNP患者和健康對照來源的免疫細胞，探討AhR-DC-Th17信號通路存在的意義，從而尋找到可能治療該疾病的新的靶點。第一部分CRSwNP患者鼻息肉組織和外周血AhR與Th17反應 相關性研究 目的：通過檢測AhR在鼻息肉組織和外周血的表達，分析其與患者全身及局部Th17反應的相關性，評估在CRSwNP患者中AhR對Th17反應的調節(jié)能力，為深入闡明CRSwNP的發(fā)病機制及為治療該疾病找到新的靶點提供相應的理論依據。 方法：收集48例CRSwNP患者（伴變應性體質組/atopic組24例；不伴變應性體質組/non-atopic組24例）的鼻息肉和外周血標本和13例腦脊液鼻漏患者（對照組）的下鼻甲粘膜和外周血標本。檢測AhR (RT-qPCR及Western blot檢測法)、RORC (RT-qPCR檢測法)、IL-17和IL-10(ELISA檢測法)的表達水平及Th17細胞的比率(流式細胞術)。 結果：CRSwNP患者鼻息肉組織和外周血中AhR的表達水平較對照組顯著降低，且atopic組的表達水平較non-atopic組更低，差異有統(tǒng)計學意義；然而，CRSwNP患者鼻息肉組織RORC水平較對照組顯著升高，外周血Th17細胞及IL-17水平亦較對照組明顯升高，且三者在atopic組的水平均較non-atopic組更高，差異具有統(tǒng)計學意義。CRSwNP患者鼻息肉組織AhR表達水平與RORC及IL-17水平均呈負相關，外周血AhR表達水平與Th17比率及IL-17水平亦呈負相關；而CRSwNP患者鼻息肉組織AhR水平與外周血AhR水平呈高度正相關，鼻息肉組織RORC及IL-17水平與外周血Th17比率及IL-17水平亦呈高度正相關。 結論：AhR的表達降低及過度的Th17反應存在于CRSwNP患者的鼻息肉組織及外周血中，由于AhR表達的降低而引起的鼻息肉組織及外周血的Th17反應在CRSwNP患者的發(fā)病機制中可能扮演著重要的角色；而atopic組表現(xiàn)為更低的AhR表達及更嚴重的Th17反應，提示變應性因素可能通過降低AhR表達從而加劇Th17反應。 第二部分AhR配體對CRSwNP患者PBMCs中Th17反應的干預調控研究 目的：通過將AhR配體ITE作為干預手段，觀察ITE干預的兩組CRSwNP患者PBMCs中AhR表達、Th17比率、IL-17和IL-10水平的變化情況，分析AhR-Th17及其相關細胞因子在CRSwNP發(fā)生發(fā)展中所扮演的角色，并在前一部分實驗基礎上，體外證實AhR配體ITE可抑制CRSwNP患者的Th17反應，從而達到在一定程度上控制炎癥的目的。 方法：收集18例CRSwNP患者（atopic組9例；non-atopic組9例）和9例腦脊液鼻漏的外周血標本，分離得到PBMCs后予以ITE干預。采用Western blot檢測兩組CRSwNP患者PBMCs中AhR表達水平；采用流式細胞術檢測PBMCs中Th17細胞比率；采用ELISA檢測PBMCs培養(yǎng)上清液中IL-17及IL-10的水平。 結果：通過ITE干預后，兩組CRSwNP患者PBMCs中AhR表達均升高，而Th17細胞比率和IL-17水平則顯著降低。此外，IL-10的水平在ITE干預后顯著升高。 結論：AhR的表達可在ITE的作用下升高，并參與抑制Th17反應和促進IL-10的產生，揭示了AhR在調控Th17反應中發(fā)揮著負調節(jié)子的功能，證實了ITE可通過AhR-Th17信號通路抑制CRSwNP患者的炎癥反應。 第三部分樹突細胞和T細胞中AhR及相關細胞因子的表達水平的研究 目的：通過檢測兩組CRSwNP患者及健康對照組外周血來源的DCs和CD4+T細胞AhR表達及相關細胞因子的分泌水平，以期找到免疫調節(jié)過程中AhR作用的靶點。 方法：收集18例CRSwNP患者（atopic組9例；non-atopic組9例）和9例健康成年人的外周血標本，通過各自磁珠分選得到單核細胞和CD4+T細胞；一方面將單核細胞通過培養(yǎng)7天誘導為DCs；另一方面直接將分選的CD4+T細胞培養(yǎng)3天。采用RT-qPCR和Western Blot方法檢測DCs和CD4+T細胞AhR的表達；；采用ELISA檢測細胞培養(yǎng)上清液中IL-1β、IL-6、IL-10、和IL-17的水平。 結果：CRSwNP患者DCs中AhR的表達水平較對照組顯著降低，且atopic組的表達水平較non-atopic組更低，差異有統(tǒng)計學意義；而三組的CD4+T細胞AhR表達無明顯差異，經過統(tǒng)計學分析差異無意思。CRSwNP患者DCs分泌促炎性細胞因子IL-1β和IL-6增加，同時抗炎性細胞因子IL-10的分泌減少；而CRSwNP患者CD4+T細胞分泌促炎性細胞因子IL-17增高，而抗炎性細胞因子IL-10的分泌降低；且atopic CRSwNP患者組和Non-atopic CRSwNP患者組細胞因子水平均存在明顯的統(tǒng)計學差異。 結論：我們的研究表明DCs中AhR的缺陷可能是導致Th17反應的靶點，AhR在DCs的活化可能在調控抗炎反應中起關鍵作用。此外，AhR的缺陷在伴有atopy的CRSwNP患者更加嚴重，這也提示我們變應性因素可能也是通過AhR信號通路進而加重CRSwNP患者的Th17反應。 第四部分AhR配體通過干預樹突細胞和T細胞抑制CRSwNP患者的Th17反應 目的：通過AhR配體ITE干預兩組CRSwNP患者外周血來源的DCs和CD4+T細胞，分析ITE通過AhR-DCs-CD4+T細胞軸和AhR-CD4+T細胞軸對Th17反應的影響。 方法：收集20例CRSwNP患者（atopic組10例；non-atopic組10例）和12例健康成年人的外周血標本，通過各自磁珠分選得到單核細胞和CD4+T細胞；一方面將單核細胞誘導為DCs，并予以ITE干預后與CD4+T細胞共培養(yǎng)；另一方面直接予以ITE干預CD4+T細胞。采用RT-qPCR方法檢測DCs和CD4+T細胞AhR的表達；采用流式細胞術檢測Th17細胞比率；采用ELISA檢測細胞培養(yǎng)上清液中IL-1β、IL-6、IL-10、和IL-17的水平。 結果：予以ITE干預DCs后,能顯著抑制DCs分泌促炎性細胞因子IL-1β和IL-6的分泌，同時促進抗炎性細胞因子IL-10的分泌；予以ITE干預CD4+T細胞后，能明顯抑制CD4+T細胞分泌促炎性細胞因子IL-17和促進抗炎性細胞因子IL-10的分泌；同時抑制Th17細胞的分化。 結論：ITE可通過作用于DCs和CD4+T細胞從而抑制Th17反應并控制CRSwNP患者的炎癥反應；AhR-DCs-Th17細胞軸可能是治療CRSwNP患者的重要信號通路。ITE作為一種無毒的AhR配體，能夠在體外明顯抑制CRSwNP患者的Th17反應，因此，它將來可能成為治療CRSwNP患者的潛在候選藥物。
[Abstract]:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinus mucosa in otolaryngology. According to the current epidemiological investigation, the incidence of CRSwNP in the world has reached 2-5%, which seriously affects the lives and lives of patients. Sleep quality and work efficiency have become one of the major public health problems of mankind, but also brought serious economic burden. Although the level of diagnosis and treatment of CRSwNP has been greatly improved, its treatment effect is still unsatisfactory to all patients, and the recurrence rate after treatment is high. In the past decades, clinical otolaryngologists At present, it is believed that the chronic inflammation of nasal cavity and sinus mucosa in CRSwNP patients is mainly caused by single or multiple factors such as abnormal anatomy, infection, allergic constitution, and abnormal immune regulation, among which Th17 The overactivation of Th17 cells and the release of inflammatory cytokines are the important reasons for the development of CRSwNP in Chinese.
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating human immune response. It has been shown to be involved in the pathogenesis of allergic and autoimmune diseases such as asthma, atopic dermatitis, experimental autoimmune encephalomyelitis and rheumatoid arthritis. Recent animal studies have also shown that AhR exerts powerful immune regulation by controlling the differentiation of T lymphocytes and dendritic cells (DCs). It is particularly noteworthy that once AhR is subjected to its natural ligands such as 2-(1-indole-3-carbonyl) -thiazole-4-carboxylic acid methyl ester (2-(1H-indole-3-carbonyl) -thiazole-4-carb Activation of oxylic acid methyl ester (ITE) can inhibit Th17 response and thus control chronic inflammation. Therefore, we hypothesize that AhR may be involved in the formation of chronic inflammation in CRSwNP patients.
The purpose of this study was to explore the role of AhR in the pathogenesis of CRSwNP patients with allergic constitution and non-allergic constitution and its correlation with Th17 reaction in CRSwNP patients. ITE was given to intervene in vitro the immune cells from CRSwNP patients and healthy controls, and to explore the significance of AhR-DC-Th17 signaling pathway in order to find possible treatment. The new target of the disease. Part I: AhR and Th17 reaction in nasal polyps and peripheral blood of CRSwNP patients
Correlation study
AIM: To investigate the expression of AhR in nasal polyps and peripheral blood, analyze its correlation with systemic and local Th17 response, and evaluate the regulation of AhR on Th17 response in patients with CRSwNP.
Methods: 48 patients with CRSwNP (24 patients with allergic constitution / atopic group; 24 patients without allergic constitution / non-atopic group) and 13 patients with cerebrospinal fluid rhinorrhea (control group) were collected for nasal polyps and peripheral blood samples. The expression level of IL-10 (ELISA assay) and the ratio of Th17 cells (flow cytometry).
Results: The expression level of AhR in nasal polyps and peripheral blood of CRSwNP patients was significantly lower than that of control group, and the expression level of AhR in atopic group was lower than that of non-atopic group. However, the RORC level in nasal polyps of CRSwNP patients was significantly higher than that of control group, and the levels of Th17 cells and IL-17 in peripheral blood were also significantly higher than that of control group. The expression of AhR in nasal polyps of CRSwNP patients was negatively correlated with RORC and IL-17 levels, and the expression of AhR in peripheral blood was negatively correlated with Th17 ratio and IL-17 level, while the level of AhR in nasal polyps of CRSwNP patients was negatively correlated with that in peripheral blood. RORC and IL-17 levels in nasal polyps were positively correlated with Th17 ratio and IL-17 level in peripheral blood.
CONCLUSION: Decreased AhR expression and excessive Th17 reaction are present in nasal polyps and peripheral blood of CRSwNP patients. Th17 reaction in nasal polyps and peripheral blood may play an important role in the pathogenesis of CRSwNP patients caused by decreased AhR expression, whereas lower expression and more severe Th17 reaction may be found in atopic patients. The Th17 reaction suggests that allergic factors may aggravate the Th17 response by decreasing the expression of AhR.
The second part is the intervention and regulation of AhR ligand on Th17 response in PBMCs of CRSwNP patients.
AIM: To observe the changes of AhR expression, Th17 ratio, IL-17 and IL-10 levels in PBMCs of two groups of CRSwNP patients treated with ITE, and to analyze the role of AhR-Th17 and its related cytokines in the development of CRSwNP. The Th17 reaction of SwNP patients can achieve the purpose of controlling inflammation to some extent.
Methods: 18 patients with CRSwNP (9 in atopic group, 9 in non-atopic group) and 9 patients with cerebrospinal fluid rhinorrhea (CSF rhinorrhea) were collected. PBMCs were isolated and treated with ITE. The expression of AhR in PBMCs was detected by Western blot, the Th17 cell ratio in PBMCs was detected by flow cytometry, and the PBMCs culture was detected by ELISA. The level of IL-17 and IL-10 in clear liquid.
Results: After ITE intervention, the expression of AhR in PBMCs of CRSwNP patients in both groups increased, while the ratio of Th17 cells and the level of IL-17 decreased significantly. In addition, the level of IL-10 increased significantly after ITE intervention.
CONCLUSION: The expression of AhR can be elevated under the action of ITE, and is involved in inhibiting Th17 response and promoting IL-10 production. It reveals that AhR plays a negative regulatory role in regulating Th17 response, which confirms that ITE can inhibit inflammation in CRSwNP patients through AhR-Th17 signaling pathway.
The third part is the expression level of AhR and related cytokines in dendritic cells and T cells.
AIM: To detect the expression of AhR and the secretion of cytokines in peripheral blood-derived DCs and CD4 + T cells from CRSwNP patients and healthy controls in order to find the target of AhR in the process of immunoregulation.
Methods: Monocytes and CD4 + T cells were isolated from peripheral blood samples of 18 patients with CRSwNP (9 cases in atopic group, 9 cases in non-atopic group) and 9 healthy adults by magnetic beads sorting. Monocytes were induced into DCs after 7 days of culture, and CD4 + T cells were cultured directly for 3 days. RT-qPCR and Western B PCR were used. The expression of AhR in DCs and CD4+T cells was detected by lot assay
Results: The expression level of AhR in DCs of CRSwNP patients was significantly lower than that of control group, and the expression level of AhR in atopic group was lower than that of non-atopic group, the difference was statistically significant; but the expression of AhR in CD4 + T cells of three groups was not significantly different, and the difference was insignificant after statistical analysis. The secretion of anti-inflammatory cytokine IL-10 decreased, while that of pro-inflammatory cytokine IL-17 and anti-inflammatory cytokine IL-10 increased in CD4+T cells of CRSwNP patients and decreased in non-atopic CRSwNP patients.
CONCLUSION: Our study suggests that the deficiency of AhR in DCs may be the target of Th17 reaction, and the activation of AhR in DCs may play a key role in regulating anti-inflammatory response. In addition, the deficiency of AhR is more serious in CRSWNP patients with atopy, suggesting that allergic factors may also aggravate CRSwNP through AhR signaling pathway. The Th17 reaction.
The fourth part of the AhR ligand inhibits the Th17 response in CRSwNP patients by interfering with dendritic cells and T cells.
AIM: To investigate the effects of AhR ligand ITE on the Th17 response of peripheral blood-derived DCs and CD4 + T cells in two groups of CRSwNP patients.
Methods: Twenty patients with CRSwNP (10 patients in atopic group; 10 patients in non-atopic group) and twelve healthy adults were collected. Monocytes and CD4 + T cells were isolated by magnetic beads. Monocytes were induced into DCs and co-cultured with CD4 + T cells after ITE intervention. The expression of AhR in DCs and CD4+T cells was detected by RT-q PCR, the ratio of Th17 cells was detected by flow cytometry, and the levels of IL-1beta, IL-6, IL-10 and IL-17 in the supernatant were detected by ELISA.
Results: ITE could significantly inhibit the secretion of pro-inflammatory cytokines IL-1beta and IL-6, and promote the secretion of anti-inflammatory cytokines IL-10. ITE could significantly inhibit the secretion of pro-inflammatory cytokine IL-17 and anti-inflammatory cytokine IL-Th10 in CD4+T cells. 7 cell differentiation.
CONCLUSION: ITE can inhibit Th17 reaction and control inflammation in CRSwNP patients by acting on DCs and CD4+T cells, and the AhR-DCs-Th17 cell axis may be an important signaling pathway in the treatment of CRSwNP patients. Potential candidate drugs for CRSwNP patients.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R765.21
本文編號：2192928
[Abstract]:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinus mucosa in otolaryngology. According to the current epidemiological investigation, the incidence of CRSwNP in the world has reached 2-5%, which seriously affects the lives and lives of patients. Sleep quality and work efficiency have become one of the major public health problems of mankind, but also brought serious economic burden. Although the level of diagnosis and treatment of CRSwNP has been greatly improved, its treatment effect is still unsatisfactory to all patients, and the recurrence rate after treatment is high. In the past decades, clinical otolaryngologists At present, it is believed that the chronic inflammation of nasal cavity and sinus mucosa in CRSwNP patients is mainly caused by single or multiple factors such as abnormal anatomy, infection, allergic constitution, and abnormal immune regulation, among which Th17 The overactivation of Th17 cells and the release of inflammatory cytokines are the important reasons for the development of CRSwNP in Chinese.
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating human immune response. It has been shown to be involved in the pathogenesis of allergic and autoimmune diseases such as asthma, atopic dermatitis, experimental autoimmune encephalomyelitis and rheumatoid arthritis. Recent animal studies have also shown that AhR exerts powerful immune regulation by controlling the differentiation of T lymphocytes and dendritic cells (DCs). It is particularly noteworthy that once AhR is subjected to its natural ligands such as 2-(1-indole-3-carbonyl) -thiazole-4-carboxylic acid methyl ester (2-(1H-indole-3-carbonyl) -thiazole-4-carb Activation of oxylic acid methyl ester (ITE) can inhibit Th17 response and thus control chronic inflammation. Therefore, we hypothesize that AhR may be involved in the formation of chronic inflammation in CRSwNP patients.
The purpose of this study was to explore the role of AhR in the pathogenesis of CRSwNP patients with allergic constitution and non-allergic constitution and its correlation with Th17 reaction in CRSwNP patients. ITE was given to intervene in vitro the immune cells from CRSwNP patients and healthy controls, and to explore the significance of AhR-DC-Th17 signaling pathway in order to find possible treatment. The new target of the disease. Part I: AhR and Th17 reaction in nasal polyps and peripheral blood of CRSwNP patients
Correlation study
AIM: To investigate the expression of AhR in nasal polyps and peripheral blood, analyze its correlation with systemic and local Th17 response, and evaluate the regulation of AhR on Th17 response in patients with CRSwNP.
Methods: 48 patients with CRSwNP (24 patients with allergic constitution / atopic group; 24 patients without allergic constitution / non-atopic group) and 13 patients with cerebrospinal fluid rhinorrhea (control group) were collected for nasal polyps and peripheral blood samples. The expression level of IL-10 (ELISA assay) and the ratio of Th17 cells (flow cytometry).
Results: The expression level of AhR in nasal polyps and peripheral blood of CRSwNP patients was significantly lower than that of control group, and the expression level of AhR in atopic group was lower than that of non-atopic group. However, the RORC level in nasal polyps of CRSwNP patients was significantly higher than that of control group, and the levels of Th17 cells and IL-17 in peripheral blood were also significantly higher than that of control group. The expression of AhR in nasal polyps of CRSwNP patients was negatively correlated with RORC and IL-17 levels, and the expression of AhR in peripheral blood was negatively correlated with Th17 ratio and IL-17 level, while the level of AhR in nasal polyps of CRSwNP patients was negatively correlated with that in peripheral blood. RORC and IL-17 levels in nasal polyps were positively correlated with Th17 ratio and IL-17 level in peripheral blood.
CONCLUSION: Decreased AhR expression and excessive Th17 reaction are present in nasal polyps and peripheral blood of CRSwNP patients. Th17 reaction in nasal polyps and peripheral blood may play an important role in the pathogenesis of CRSwNP patients caused by decreased AhR expression, whereas lower expression and more severe Th17 reaction may be found in atopic patients. The Th17 reaction suggests that allergic factors may aggravate the Th17 response by decreasing the expression of AhR.
The second part is the intervention and regulation of AhR ligand on Th17 response in PBMCs of CRSwNP patients.
AIM: To observe the changes of AhR expression, Th17 ratio, IL-17 and IL-10 levels in PBMCs of two groups of CRSwNP patients treated with ITE, and to analyze the role of AhR-Th17 and its related cytokines in the development of CRSwNP. The Th17 reaction of SwNP patients can achieve the purpose of controlling inflammation to some extent.
Methods: 18 patients with CRSwNP (9 in atopic group, 9 in non-atopic group) and 9 patients with cerebrospinal fluid rhinorrhea (CSF rhinorrhea) were collected. PBMCs were isolated and treated with ITE. The expression of AhR in PBMCs was detected by Western blot, the Th17 cell ratio in PBMCs was detected by flow cytometry, and the PBMCs culture was detected by ELISA. The level of IL-17 and IL-10 in clear liquid.
Results: After ITE intervention, the expression of AhR in PBMCs of CRSwNP patients in both groups increased, while the ratio of Th17 cells and the level of IL-17 decreased significantly. In addition, the level of IL-10 increased significantly after ITE intervention.
CONCLUSION: The expression of AhR can be elevated under the action of ITE, and is involved in inhibiting Th17 response and promoting IL-10 production. It reveals that AhR plays a negative regulatory role in regulating Th17 response, which confirms that ITE can inhibit inflammation in CRSwNP patients through AhR-Th17 signaling pathway.
The third part is the expression level of AhR and related cytokines in dendritic cells and T cells.
AIM: To detect the expression of AhR and the secretion of cytokines in peripheral blood-derived DCs and CD4 + T cells from CRSwNP patients and healthy controls in order to find the target of AhR in the process of immunoregulation.
Methods: Monocytes and CD4 + T cells were isolated from peripheral blood samples of 18 patients with CRSwNP (9 cases in atopic group, 9 cases in non-atopic group) and 9 healthy adults by magnetic beads sorting. Monocytes were induced into DCs after 7 days of culture, and CD4 + T cells were cultured directly for 3 days. RT-qPCR and Western B PCR were used. The expression of AhR in DCs and CD4+T cells was detected by lot assay
Results: The expression level of AhR in DCs of CRSwNP patients was significantly lower than that of control group, and the expression level of AhR in atopic group was lower than that of non-atopic group, the difference was statistically significant; but the expression of AhR in CD4 + T cells of three groups was not significantly different, and the difference was insignificant after statistical analysis. The secretion of anti-inflammatory cytokine IL-10 decreased, while that of pro-inflammatory cytokine IL-17 and anti-inflammatory cytokine IL-10 increased in CD4+T cells of CRSwNP patients and decreased in non-atopic CRSwNP patients.
CONCLUSION: Our study suggests that the deficiency of AhR in DCs may be the target of Th17 reaction, and the activation of AhR in DCs may play a key role in regulating anti-inflammatory response. In addition, the deficiency of AhR is more serious in CRSWNP patients with atopy, suggesting that allergic factors may also aggravate CRSwNP through AhR signaling pathway. The Th17 reaction.
The fourth part of the AhR ligand inhibits the Th17 response in CRSwNP patients by interfering with dendritic cells and T cells.
AIM: To investigate the effects of AhR ligand ITE on the Th17 response of peripheral blood-derived DCs and CD4 + T cells in two groups of CRSwNP patients.
Methods: Twenty patients with CRSwNP (10 patients in atopic group; 10 patients in non-atopic group) and twelve healthy adults were collected. Monocytes and CD4 + T cells were isolated by magnetic beads. Monocytes were induced into DCs and co-cultured with CD4 + T cells after ITE intervention. The expression of AhR in DCs and CD4+T cells was detected by RT-q PCR, the ratio of Th17 cells was detected by flow cytometry, and the levels of IL-1beta, IL-6, IL-10 and IL-17 in the supernatant were detected by ELISA.
Results: ITE could significantly inhibit the secretion of pro-inflammatory cytokines IL-1beta and IL-6, and promote the secretion of anti-inflammatory cytokines IL-10. ITE could significantly inhibit the secretion of pro-inflammatory cytokine IL-17 and anti-inflammatory cytokine IL-Th10 in CD4+T cells. 7 cell differentiation.
CONCLUSION: ITE can inhibit Th17 reaction and control inflammation in CRSwNP patients by acting on DCs and CD4+T cells, and the AhR-DCs-Th17 cell axis may be an important signaling pathway in the treatment of CRSwNP patients. Potential candidate drugs for CRSwNP patients.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R765.21
【共引文獻】
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