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Research Article

精神分裂症患者罕见的白细胞介素-15的受体α变异干扰信号传导

卷 19, 期 8, 2019

页: [560 - 569] 页: 10

弟呕挨: 10.2174/1566524019666190617172054

价格: $65

摘要

背景：精神分裂症是一种复杂、衰弱的精神疾病，遗传力强。其发病机制与免疫调节失调有关。白细胞介素15和白细胞介素15受体α(IL-15Rα)是经典的免疫分子。他们也有助于维持正常的大脑功能，导致我们假设IL-15Rα基因(IL-15RA)变异与精神分裂症的发病有关。 目的：探讨IL-15 RA的基因变异是否与精神分裂症的发生发展有关，以及IL-15 RA单核苷酸多态性(Snp)是否在下游信号转导中发挥重要作用。 方法和结果：我们对132例中国精神分裂症患者的IL-15RA外显子进行了测序，并在一例诊断为紧张性精神分裂症和强直性脊椎炎（AS）的患者中鉴定了一个罕见的变异体(Rs 528238821)。 我们在PBI-CMV载体驱动的细胞中过度表达了这一错义变异.细胞在白细胞介素15的作用下STAT 3的磷酸化减弱。 结论：IL-15RA突变在精神分裂症患者中很少见，但对IL-15Rα细胞内信号转导有干扰作用。考虑到紧张性精神分裂症状和IL-15Rα基因敲除小鼠的N表型具有相似性、基因变异对精神分裂症亚型有诊断价值。

关键词: 白细胞介素—15受体α，白细胞介素——15，单核苷酸多态性，精神分裂症，IL-15RA，STAT 3磷酸化。

« Previous Next »
[1]
Stefansson H, Meyer-Lindenberg A, Steinberg S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 2014; 505(7483): 361-6.
[http://dx.doi.org/10.1038/nature12818] [PMID: 24352232]
[2]
Sullivan PF, Magnusson C, Reichenberg A, et al. Family history of schizophrenia and bipolar disorder as risk factors for autism. Arch Gen Psychiatry 2012; 69(11): 1099-103.
[http://dx.doi.org/10.1001/archgenpsychiatry.2012.730] [PMID: 22752149]
[3]
Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: Update 2012. Mol Psychiatry 2012; 17(12): 1228-38.
[http://dx.doi.org/10.1038/mp.2012.23] [PMID: 22488257]
[4]
McClellan J, King MC. Genetic heterogeneity in human disease. Cell 2010; 141(2): 210-7.
[http://dx.doi.org/10.1016/j.cell.2010.03.032] [PMID: 20403315]
[5]
Duncan LE, Ratanatharathorn A, Aiello AE, et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry 2018; 23(3): 666-73.
[http://dx.doi.org/10.1038/mp.2017.77] [PMID: 28439101]
[6]
Schizophrenia working group of the psychiatric genomics consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511(7510): 421-7.
[http://dx.doi.org/10.1038/nature13595] [PMID: 25056061]
[7]
Moises HW, Yang L, Kristbjarnarson H, et al. An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat Genet 1995; 11(3): 321-4.
[http://dx.doi.org/10.1038/ng1195-321] [PMID: 7581457]
[8]
Hoischen A, Krumm N, Eichler EE. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci 2014; 17(6): 764-72.
[http://dx.doi.org/10.1038/nn.3703] [PMID: 24866042]
[9]
Malherbe PJ, Roos JL Jr, Ehlers R, Karayiorgou M, Roos JL. Phenotypic features of patients with schizophrenia carrying de novo gene mutations: a pilot study. Psychiatry Res 2015; 225(1-2): 108-14.
[http://dx.doi.org/10.1016/j.psychres.2014.10.024] [PMID: 25467704]
[10]
Wang Q, Li M, Yang Z, et al. Increased co-expression of genes harboring the damaging de novo mutations in Chinese schizophrenic patients during prenatal development. Sci Rep 2015; 5: 18209.
[http://dx.doi.org/10.1038/srep18209] [PMID: 26666178]
[11]
Hudson ZD, Miller BJ. Meta-Analysis of Cytokine and Chemokine Genes in Schizophrenia. Clin Schizophr Relat Psychoses 2018; 12(3): 121-129B.
[http://dx.doi.org/10.3371/CSRP.HUMI.070516] [PMID: 27454212]
[12]
Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000; 157(5): 683-94.
[http://dx.doi.org/10.1176/appi.ajp.157.5.683] [PMID: 10784457]
[13]
Martinuzzi E, Barbosa S, Daoudlarian D, et al. OPTiMiSE Study Group. Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study. Transl Psychiatry 2019; 9(1): 20.
[http://dx.doi.org/10.1038/s41398-018-0366-5] [PMID: 30655509]
[14]
Pan W, Wu X, Kastin AJ, et al. Potential protective role of IL15Rα during inflammation. J Mol Neurosci 2011; 43(3): 412-23.
[http://dx.doi.org/10.1007/s12031-010-9459-1] [PMID: 20981579]
[15]
Pan W, Wu X, He Y, et al. Brain interleukin-15 in neuroinflammation and behavior. Neurosci Biobehav Rev 2013; 37(2): 184-92.
[http://dx.doi.org/10.1016/j.neubiorev.2012.11.009] [PMID: 23201098]
[16]
Patidar M, Yadav N, Dalai SK. Interleukin 15: A key cytokine for immunotherapy. Cytokine Growth Factor Rev 2016; 31: 49-59.
[http://dx.doi.org/10.1016/j.cytogfr.2016.06.001] [PMID: 27325459]
[17]
Pilipow K, Roberto A, Roederer M, Waldmann TA, Mavilio D, Lugli E. IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy. Cancer Res 2015; 75(24): 5187-93.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1498] [PMID: 26627006]
[18]
de Jong JL, Farner NL, Widmer MB, Giri JG, Sondel PM. Interaction of IL-15 with the shared IL-2 receptor beta and gamma c subunits. The IL-15/beta/gamma c receptor-ligand complex is less stable than the IL-2/beta/gamma c receptor-ligand complex. J Immunol 1996; 156(4): 1339-48.
[PMID: 8568232]
[19]
Giri JG, Ahdieh M, Eisenman J, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 1994; 13(12): 2822-30.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06576.x] [PMID: 8026467]
[20]
Kurowska M, Rudnicka W, Maślińska D, Maśliński W. Expression of IL-15 and IL-15 receptor isoforms in select structures of human fetal brain. Ann N Y Acad Sci 2002; 966: 441-5.
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb04245.x] [PMID: 12114302]
[21]
He Y, Wu X, Khan RS, et al. IL-15 receptor deletion results in circadian changes of locomotor and metabolic activity. J Mol Neurosci 2010; 41(2): 315-21.
[http://dx.doi.org/10.1007/s12031-009-9319-z] [PMID: 20012227]
[22]
Pistilli EE, Bogdanovich S, Garton F, et al. Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 2011; 121(8): 3120-32.
[http://dx.doi.org/10.1172/JCI44945] [PMID: 21765213]
[23]
Wu X, Hsuchou H, Kastin AJ, et al. Interleukin-15 affects serotonin system and exerts antidepressive effects through IL15Rα receptor. Psychoneuroendocrinology 2011; 36(2): 266-78.
[http://dx.doi.org/10.1016/j.psyneuen.2010.07.017] [PMID: 20724079]
[24]
Wu X, He Y, Hsuchou H, Kastin AJ, Rood JC, Pan W. Essential role of interleukin-15 receptor in normal anxiety behavior. Brain Behav Immun 2010; 24(8): 1340-6.
[http://dx.doi.org/10.1016/j.bbi.2010.06.012] [PMID: 20600810]
[25]
Nguyen L, Bohlen J, Stricker J, Chahal I, Zhang H, Pistilli EE. Hippocampus-specific deficiency of IL-15Rα contributes to greater anxiety-like behaviors in mice. Metab Brain Dis 2017; 32(2): 297-302.
[http://dx.doi.org/10.1007/s11011-016-9930-y] [PMID: 27837366]
[26]
He Y, Hsuchou H, Wu X, et al. Interleukin-15 receptor is essential to facilitate GABA transmission and hippocampal-dependent memory. J Neurosci 2010; 30(13): 4725-34.
[http://dx.doi.org/10.1523/JNEUROSCI.6160-09.2010] [PMID: 20357123]
[27]
Souza-Fonseca-Guimaraes F, Parlato M, de Oliveira RB, et al. Interferon-γ and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING). J Biol Chem 2013; 288(15): 10715-21.
[http://dx.doi.org/10.1074/jbc.M112.435602] [PMID: 23443666]
[28]
Wilkie S, Burbridge SE, Chiapero-Stanke L, et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J Biol Chem 2010; 285(33): 25538-44.
[http://dx.doi.org/10.1074/jbc.M110.127951] [PMID: 20562098]
[29]
Huntington ND, Puthalakath H, Gunn P, et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 2007; 8(8): 856-63.
[http://dx.doi.org/10.1038/ni1487] [PMID: 17618288]
[30]
Waldmann T, Tagaya Y, Bamford R. Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol 1998; 16(3-4): 205-26.
[http://dx.doi.org/10.3109/08830189809042995] [PMID: 9505189]
[31]
Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009; 461(7265): 747-53.
[http://dx.doi.org/10.1038/nature08494] [PMID: 19812666]
[32]
Wu X, Pan W, He Y, et al. Cerebral interleukin-15 shows upregulation and beneficial effects in experimental autoimmune encephalomyelitis. J Neuroimmunol 2010; 223: 65-72. 36.
[33]
Wu X, Kastin AJ, Hsuchou H, Pan W. The effects of IL2Rgamma knockout on depression and contextual memory. Behav Brain Res 2010; 213(2): 319-22.
[http://dx.doi.org/10.1016/j.bbr.2010.04.046] [PMID: 20438766]
[34]
Pan W, Yu C, Hsuchou H, Kastin AJ. The role of cerebral vascular NFkappaB in LPS-induced inflammation: differential regulation of efflux transporter and transporting cytokine receptors. Cell Physiol Biochem 2010; 25(6): 623-30.
[http://dx.doi.org/10.1159/000315081] [PMID: 20511707]
[35]
Cosman D. The hematopoietin receptor superfamily. Cytokine 1993; 5(2): 95-106.
[http://dx.doi.org/10.1016/1043-4666(93)90047-9] [PMID: 8392875]
[36]
Pan W, Stone KP, Hsuchou H, Manda VK, Zhang Y, Kastin AJ. Cytokine signaling modulates blood-brain barrier function. Curr Pharm Des 2011; 17(33): 3729-40.
[http://dx.doi.org/10.2174/138161211798220918] [PMID: 21834767]
[37]
Stone KP, Kastin AJ, Pan W. NFĸB is an unexpected major mediator of interleukin-15 signaling in cerebral endothelia. Cell Physiol Biochem 2011; 28(1): 115-24.
[http://dx.doi.org/10.1159/000331720] [PMID: 21865854]
[38]
Ouyang S, Hsuchou H, Kastin AJ, Pan W. TNF stimulates nuclear export and secretion of IL-15 by acting on CRM1 and ARF6. PLoS One 2013; 8(8)e69356
[http://dx.doi.org/10.1371/journal.pone.0069356] [PMID: 23950892]
[39]
Volk DW, Gonzalez-Burgos G, Lewis DA. l-Proline, GABA Synthesis and Gamma Oscillations in Schizophrenia. Trends Neurosci 2016; 39(12): 797-8.
[http://dx.doi.org/10.1016/j.tins.2016.10.009] [PMID: 27832914]
[40]
Kim JH, Kim JH, Son YD, et al. Altered interregional correlations between serotonin transporter availability and cerebral glucose metabolism in schizophrenia: A high-resolution PET study using [11C]DASB and [18F]FDG. Schizophr Res 2017; 182: 55-65.
[http://dx.doi.org/10.1016/j.schres.2016.10.020] [PMID: 27760700]
[41]
Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 2000; 191: 771-80. 33.
[42]
Lodolce J, Burkett P, Koka R, et al. Interleukin-15 and the regulation of lymphoid homeostasis. Mol Immunol 2002; 39: 537-44. 34
[43]
Pan W, Yu C, Hsuchou H, Khan RS, Kastin AJ. Cerebral microvascular IL15 is a novel mediator of TNF action. J Neurochem 2009; 111(3): 819-27.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06371.x] [PMID: 19719822]
[44]
Hou MS, Huang ST, Tsai MH, et al. The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus. J Autoimmun 2015; 56: 118-29. 35.
[45]
Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163(3): 521-8.
[http://dx.doi.org/10.1176/appi.ajp.163.3.521] [PMID: 16513876]

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