胰岛素样生长因子1-磷脂酰肌醇3激酶/哺乳动物雷帕霉素靶蛋白通路对T细胞与角质形成细胞共培养模型中炎性细胞因子的影响
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摘要
目的:检测在口腔扁平苔藓中异常活化的胰岛素样生长因子1-磷脂酰肌醇3激酶/哺乳动物雷帕霉素靶蛋白(insulin-like growth factor 1-phosphatidylinositol-3-kinase/the mammalian target of rapamycin,IGF1-PI3K/mTOR)信号通路对T细胞与角质形成细胞共培养环境中炎性细胞因子的影响。方法:通过外源性IGF1、LY294002、雷帕霉素评估IGF-PI3K/mTOR信号通路在活化T细胞中的作用,构建T细胞与角质形成细胞共培养模型,运用酶联免疫吸附试验(enzyme-linked immunosorbnent assay,ELISA)法检测细胞培养上清中白细胞介素-2(interleukin-2,IL-2)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)分泌情况。结果:与单独培养的T细胞比较,T细胞与角质形成细胞共培养能促进TNF-α的分泌(P<0.05),而对IL-2的分泌无明显影响;而IGF1-PI3K/mTOR通路可减少共培养环境中IL-2和TNF-α水平(P<0.05)。结论:IGF1-PI3K/mTOR信号通路可调控T细胞与角质形成细胞共培养模型中炎性细胞因子的分泌,可能参与了口腔扁平苔藓免疫炎症的发生发展。
Objective: To investigate the influence of IGF1-PI3 K/MTOR signaling pathway, which was abnormally activated in OLP, on the inflammatory cytokines in the interaction of T cells and keratinocytes in oral lichen planus(OLP). Methods: A transwell co-culture system composed of T cells and oral keratinocytes was used as a model of OLP in vitro. The effects of activated T cells pretreated with LY294002, rapamycin, and IGF1 on the levels of IL-2 and TNF-α in supernatant from T cell alone and co-culture system were detected via ELISA, respectively. Results: Compared to the T cells cultured alone, the interaction of keratinocytes and T cells could increase the secretion of TNF-α(P<0.05), but has no impact on the level of IL-2. Whereas the aberrant IGF1-PI3 K/MTOR signaling decreased the IL-2 and TNF-α secretion in the co-culture system(P<0.05). Conclusion: The IGF1-PI3 K/MTOR signaling may modulate the cytokine networks in the crosstalk between T cells and keratinocytes and participate in the progression of OLP.
Objective: To investigate the influence of IGF1-PI3 K/MTOR signaling pathway, which was abnormally activated in OLP, on the inflammatory cytokines in the interaction of T cells and keratinocytes in oral lichen planus(OLP). Methods: A transwell co-culture system composed of T cells and oral keratinocytes was used as a model of OLP in vitro. The effects of activated T cells pretreated with LY294002, rapamycin, and IGF1 on the levels of IL-2 and TNF-α in supernatant from T cell alone and co-culture system were detected via ELISA, respectively. Results: Compared to the T cells cultured alone, the interaction of keratinocytes and T cells could increase the secretion of TNF-α(P<0.05), but has no impact on the level of IL-2. Whereas the aberrant IGF1-PI3 K/MTOR signaling decreased the IL-2 and TNF-α secretion in the co-culture system(P<0.05). Conclusion: The IGF1-PI3 K/MTOR signaling may modulate the cytokine networks in the crosstalk between T cells and keratinocytes and participate in the progression of OLP.
引文
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[10] Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases [J]. Pharmacol Rev, 2010, 62(2): 199-236.
[11] Guo J, Zheng D, Li WF, et al. Insulin-like growth factor 1 treatment of MSCs attenuates inflammation and cardiac dysfunction following MI [J]. Inflammation, 2014, 37(6): 2156-2163.
[12] Zhang N, Zhang J, Tan YQ, et al. Activated Akt/mTOR-autophagy in local T cells of oral lichen planus [J]. Int Immunopharmacol, 2017, 48:84-90.
[13] Tan YQ, Zhang J, Du GF, et al. Altered autophagy-associated genes expression in T cells of oral lichen planus correlated with clinical features [J]. Mediators Inflamm, 2016, 2016:4867368.
[14] Malek T, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity [J]. Immunity, 2010, 33(2): 153-165.
[15] Lu R, Zhang J, Sun W, et al. Inflammation-related cytokines in oral lichen planus: an overview [J]. J Oral Pathol Med, 2015, 44(1): 1-14.
[16] Humberto J, Pavanin J, Rocha M, et al. Cytokines, cortisol, and nitric oxide as salivary biomarkers in oral lichen planus: a systematic review [J]. Braz Oral Res, 2018, 32: e82.
[17] Alrashdan MS, Cirillo N, Mccullough M. Oral lichen planus: a literature review and update [J]. Arch Dermatol Res, 2016, 308(8): 539-551.
[18] Cao G, Wang Q, Li G, et al. mTOR inhibition potentiates cytotoxicity of Vgamma4 gammadelta T cells via up-regulating NKG2D and TNF-alpha [J]. J Leukoc Biol, 2016, 100(5): 1181-1189.
[2] Gupta S, Jawanda MK. Oral lichen planus: an update on etiology, pathogenesis, clinical presentation, diagnosis and management [J]. Indian J Dermatol, 2015, 60(3): 222-229.
[3] Payeras MR, Cherubini K, Figueiredo MA, et al. Oral lichen planus: focus on etiopathogenesis [J]. Arch Oral Biol, 2013, 58(9): 1057-1069.
[4] Zhang J, Tan YQ, Wei MH, et al. TLR4-induced B7-H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus [J]. Exp Dermatol, 2017, 26(5): 409-415.
[5] Stark AK, Sriskantharajah S, Hessel EM, et al. PI3K inhibitors in inflammation, autoimmunity and cancer [J]. Curr Opin Pharmacol, 2015, 23: 82-91.
[6] Fruman D, Chiu H, Hopkins B, et al. The PI3K pathway in human disease [J]. Cell, 2017, 170(4): 605-635.
[7] Be Liu AN, Pistol G, Marica CM, et al. PI3K/Akt signaling in peripheral T lymphocytes from systemic lupus erythematosus patients [J]. Roum Arch Microbiol Immunol, 2009, 68(2): 69-79.
[8] Erasalo H, Laavola M, Hamalainen M, et al. PI3K inhibitors LY294002 and IC87114 reduce inflammation in carrageenan-induced paw oedema and down-regulate inflammatory gene expression in activated macrophages [J]. Basic Clin Pharmacol Toxicol, 2015, 116(1): 53-61.
[9] Liu Y, Zhang DT, Liu XG. mTOR signaling in T cell immunity and autoimmunity [J]. Int Rev Immunol, 2015, 34(1): 50-66.
[10] Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases [J]. Pharmacol Rev, 2010, 62(2): 199-236.
[11] Guo J, Zheng D, Li WF, et al. Insulin-like growth factor 1 treatment of MSCs attenuates inflammation and cardiac dysfunction following MI [J]. Inflammation, 2014, 37(6): 2156-2163.
[12] Zhang N, Zhang J, Tan YQ, et al. Activated Akt/mTOR-autophagy in local T cells of oral lichen planus [J]. Int Immunopharmacol, 2017, 48:84-90.
[13] Tan YQ, Zhang J, Du GF, et al. Altered autophagy-associated genes expression in T cells of oral lichen planus correlated with clinical features [J]. Mediators Inflamm, 2016, 2016:4867368.
[14] Malek T, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity [J]. Immunity, 2010, 33(2): 153-165.
[15] Lu R, Zhang J, Sun W, et al. Inflammation-related cytokines in oral lichen planus: an overview [J]. J Oral Pathol Med, 2015, 44(1): 1-14.
[16] Humberto J, Pavanin J, Rocha M, et al. Cytokines, cortisol, and nitric oxide as salivary biomarkers in oral lichen planus: a systematic review [J]. Braz Oral Res, 2018, 32: e82.
[17] Alrashdan MS, Cirillo N, Mccullough M. Oral lichen planus: a literature review and update [J]. Arch Dermatol Res, 2016, 308(8): 539-551.
[18] Cao G, Wang Q, Li G, et al. mTOR inhibition potentiates cytotoxicity of Vgamma4 gammadelta T cells via up-regulating NKG2D and TNF-alpha [J]. J Leukoc Biol, 2016, 100(5): 1181-1189.