白细胞介素-1β与外伤后癫痫发生的联系——一个遗传学和生物标记物的队列研究_Journal of Epilepsy

Authors：

 徐秦岚 , 杨华俊 ,  王群

首都医科大学附属北京天坛医院神经病学中心癫痫科 (北京, 100050);

Corresponding author：

王群, Email: wangq@ccmu.edu.cn

Keywords：

外伤后癫痫; 炎症; 创伤性脑损伤; 遗传变异; IL-1β

DOI：

10.7507/2096-0247.20150044

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外伤后癫痫(Post-traumatic epilepsy, PTE)是创伤性脑损伤(Traumatic brain injury, TBI)后的一个主要的并发症, 但遗传变异在调节PTE发生中的作用尚不清楚。假设TBI诱导的炎症可能是导致癫痫发生的原因, 对白细胞介素-1β(Interleukin-1β, IL-1β)基因的遗传变异情况, 脑脊液和血清中IL-1β水平和IL-1β的脑脊液/血清比值能否预测TBI后PTE的发生进行了评估。共调查了256例中度至重度TBI后患PTE的成年白种人。对IL-1β标记和功能性单核苷酸多态性(SNPs)进行基因分型。对遗传变异性和PTE的发生进行评估。在调查患者中抽取一部分患者(n=59)在其外伤后1周内收集血清和脑脊液的IL-1β, 并评估它们与IL-1β基因变异及PTE的关系。临时配对IL-1β的脑脊液/血清比值以反映血清IL-1β水平对脑脊液IL-1β的影响。多变量分析显示随着时间推移, 高脑脊液/血清IL-1β比值与PTE风险增加有关(P=0.008)。rs1143634的多变量分析揭示了CT基因型与PTE风险增加有关(P=0.005)。CT基因型组其血清IL-1β水平较低(P=0.014), 脑脊液/血清IL-1β比值较高(P=0.093)。这是第一个揭示PTE风险中的IL-1β基因变异, 及TBI后IL-1β基因变异与血清IL-1β水平的关系和IL-1β比值与PTE风险的关系。根据这些发现, 提出基因和IL-1β比值与PTE的相关性可能归因于TBI恢复期的血脑屏障完整性的生物变异性包括。为进一步的研究提供了理论依据, 验证遗传变异性对TBI后IL-1β产生的影响, 评估造成脑脊液/血清IL-1β比值与PTE相关性的基因介导的信号传导机制, 及评估减少PTE的靶向IL-1β治疗。

Citation： 徐秦岚, 杨华俊, 王群. 白细胞介素-1β与外伤后癫痫发生的联系——一个遗传学和生物标记物的队列研究. Journal of Epilepsy, 2015, 1(3): 261-271. doi: 10.7507/2096-0247.20150044 Copy

1.	Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures:a prospective, multicenter investigation. Arch Phys Med Rehabil, 2003, 84(21):365-373.
2.	Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia, 2003, 44(12):18-20.
3.	Annegers JF, Hauser WA, Coan SP, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med, 1998, 338(30):20-24.
4.	Englander J, Bushnik T, Wright JM, et al. Mortality in late posttraumatic seizures. J Neurotrauma, 2009, 26(11):1471-1477.
5.	Kolakowsky-Hayner SA, Wright J, Englander J, et al. Impact of late post-traumatic seizures on physical health and functioning for individuals with brain injury within the community. Brain Inj, 2013, 27(6):578-586.
6.	Formisano R, Barba C, Buzzi MG, et al. The impact of prophylactic treatment on post-traumatic epilepsy after severe traumatic brain injury. Brain Inj, 2007, 21(8):499-504.
7.	Vezzani A, Ravizza T, Balosso S, et al. Glia as a source of cytokines:implications for neuronal excitability and survival. Epilepsia, 2008, 49 (Suppl 2):24-32.
8.	Holtman L, van Vliet EA, Aronica E, et al. Blood plasma inflammation markers during epileptogenesis in post-status epilepticus rat model for temporal lobe epilepsy. Epilepsia, 2013, 54(20):589-595.
9.	Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci, 2005, 8(3):752-758.
10.	Ferrari D, Villalba M, Chiozzi P, et al. Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol, 1996, 156(28):1531-1539.
11.	Lu KT, Wang YW, Yang JT, et al. Effect of interleukin-1 on traumatic brain injury-induced damage to hippocampal neurons. J Neurotrauma, 2005, 22(10):885-895.
12.	Johnson VE, Stewart JE, Begbie FD, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain, 2013, 135(34):28-42.
13.	Smith DH, Chen XH, Pierce JE, et al. Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma, 1997, 14(5):715-727.
14.	Zhu G, Okada M, Yoshida S, et al. Effects of interleukin-1beta on hippocampal glutamate and GABA releases associated with Ca²⁺-induced Ca²⁺ releasing systems. Epilepsy Res, 2006, 71(10):107-116.
15.	Vezzani A, Moneta D, Conti M, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA, 2000, 97(16):11534-11539.
16.	Ravizza T, Lucas SM, Balosso S, et al. Inactivation of caspase-1 in rodent brain:a novel anticonvulsive strategy. Epilepsia, 2006, 47(16):1160-1168.
17.	Rijkers H, Majoie HJ, Hoogland G, et al. The role of interleukin-1 in seizures and epilepsy:a critical review. Exp Neurol, 2009, 216(112):258-271.
18.	Darrah SD, Miller MA, Ren D, et al. Genetic variability in glutamic acid decarboxylase genes:associations with post-traumatic seizures after severe TBI. Epilepsy Res, 2013, 103(20):180-194.
19.	Wagner AK, Miller MA, Scanlon J, et al. Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI. Epilepsy Res, 2010, 90(11):259-272.
20.	Kauffman MA, Moron DG, Consalvo D, et al. Association study between interleukin 1 beta gene and epileptic disorders:a HuGe review and meta-analysis. Genet Med, 2008, 10(5):83-88.
21.	Hall SK, Perregaux DG, Gabel CA, et al. Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum, 2004, 50(12):1976-1983.
22.	Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy:definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 2005, 46(21):470-472.
23.	Bratton SL, Bullock RM, Carney N, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma, 2007, 24(6):s 37-44.
24.	Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, doubleblind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med, 1990, 323(25):497-502.
25.	Gennarelli TA, Wodzin E. AIS 2005:a contemporary injury scale. Injury, 2006, 37(11):1083-1091.
26.	Baker SP, O'Neill B, Haddon WJr, et al. The injury severity score:a method for describing patients with multiple injuries and evaluating emergency care. J Trauma, 1974, 14(3):187-196.
27.	Berry C, Ley EJ, Tillou A, et al. The effect of gender on patients with moderate to severe head injuries. J Trauma, 2009, 67(13):950-953.
28.	Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 1988, 16(9):1215.
29.	Mellergard P, Aneman O, Sjogren F, et al. Differences in cerebral extracellular response of interleukin-1b, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe trauma in humans. Neurosurgery, 2011, 68(21):12-19.
30.	Camargo MC, Mera R, Correa P, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer:a meta-analysis. Cancer Epidemiol Biomarkers Prev, 2006, 15(11):1674-1687.
31.	National Institute of Neurological Disorders and Stroke. Epilepsy research benchmarks progress report 2007-2012. NINDS Online, 2013, 9(4):1-59.
32.	Zou H, Brayer SW, Hurwitz M, et al. Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury. Neurorehabil Neural Repair, 2013, 27:878-888. Epilepsia, 2014, 55(7):1109-1119.
33.	Omran A, Peng J, Zhang C, et al. Interleukin-1b and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. Epilepsia, 2012, 53(8):1215-1224.
34.	Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol, 2005, 5(2):629-640.
35.	Acosta SA, Tajiri N, Shinozuka K, et al. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. Plos One, 2013, 8(2):e53376.
36.	Boles J, Goyal A, Kumar R, et al. Chronic inflammation after severe traumatic brain injury:characterization and associations with outcome. Presented at Annual Symposium of the National Neurotrauma Society, 2012, 7(1):22-25.
37.	Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuro Inflammation, 2012, 9(3):236.
38.	Skinner RA, Gibson RM, Rothwell NJ, et al. Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol, 2009, 156(23):1115-1123.
39.	Aibiki M, Maekawa S, Ogura S, et al. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma, 1999, 16(10):225-232.
40.	Helmy A, Carpenter KLH, Menon DK, et al. The cytokine response to human traumatic brain injury:temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab, 2011, 31(12):658-670.
41.	Lee SC, Liu W, Dickson DW, et al. Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol, 1993, 150(21):2659-2667.
42.	Brown R, Li Z, Vriend CY, et al. Suppression of splenic macrophage interleukin-1 secretion following intracerebroventricular injection of interleukin-1 beta:evidence for pituitary-adrenal and sympathetic control. Cell Immunol, 1991, 132(23):84-93.
43.	Van der Zee CE, Rashid K, Le K, et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J Neurosci, 1995, 15(7):5316-5323.
44.	Spranger M, Lindholm D, Bandtlow C, et al. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system:comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur J Neurosci, 1990, 2(1):69-76.
45.	DeKosky ST, Goss JR, Miller PD, et al. Upregulation of nerve growth factor following cortical trauma. Exp Neurol, 1994, 130(60):173-177.
46.	DeKosky ST, Styren SD, O'Malley ME, et al. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain. Ann Neurol, 1996, 39(12):123-127.
47.	von Wedel-Parlow M, Wolte P, Galla HJ, et al. Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro. J Neurochem, 2009, 111(15):111-118.
48.	Pociot F, Mølvig J, Wogensen L, et al. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest, 1992, 22(9):396-402.
49.	Santarsieri M, Niyonkuru C, McCullough EH, et al. Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury. J Neurotrauma, 2014, 31(5):699-712.
50.	Schmitz G, Kaminski WE, Porsch-Ozcurumez M, et al. ATPbinding cassette transporter A1 (ABCA1) in macrophages:a dual function in inflammation and lipid metabolism. Pathobiology, 1999, 67(11):236-240.
51.	Hamon Y, Luciani MF, Becq F, et al. Interleukin-1beta secretion is impaired by inhibitors of the ATP bind cassette transport, ABC1. Blood, 1997, 90(16):2911-2915.
52.	Gao WM, Chadha MS, Kline AE, et al. Immunohistochemical analysis of histone H3 acetylation and methylation-evidence for altered epigenetic signaling following traumatic brain injury in immature rats. Brain Res, 2006, 1070(221):31-34.
53.	Chen H, Wilkins LM, Aziz N, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet, 2006, 15(7):519-529.
54.	Chen X, El Gazzar M, Yoza BK, et al. The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. J Biol Chem, 2009, 284(18):27857-27865.
55.	Dominici R, Malferrari G, Mariani C, et al. The Interleukin 1-beta exonic (+3953) polymorphism does not alter in vitro protein secretion. Exp Mol Pathol, 2002, 73(21):139-141.

1. Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures:a prospective, multicenter investigation. Arch Phys Med Rehabil, 2003, 84(21):365-373.
2. Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia, 2003, 44(12):18-20.
3. Annegers JF, Hauser WA, Coan SP, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med, 1998, 338(30):20-24.
4. Englander J, Bushnik T, Wright JM, et al. Mortality in late posttraumatic seizures. J Neurotrauma, 2009, 26(11):1471-1477.
5. Kolakowsky-Hayner SA, Wright J, Englander J, et al. Impact of late post-traumatic seizures on physical health and functioning for individuals with brain injury within the community. Brain Inj, 2013, 27(6):578-586.
6. Formisano R, Barba C, Buzzi MG, et al. The impact of prophylactic treatment on post-traumatic epilepsy after severe traumatic brain injury. Brain Inj, 2007, 21(8):499-504.
7. Vezzani A, Ravizza T, Balosso S, et al. Glia as a source of cytokines:implications for neuronal excitability and survival. Epilepsia, 2008, 49 (Suppl 2):24-32.
8. Holtman L, van Vliet EA, Aronica E, et al. Blood plasma inflammation markers during epileptogenesis in post-status epilepticus rat model for temporal lobe epilepsy. Epilepsia, 2013, 54(20):589-595.
9. Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci, 2005, 8(3):752-758.
10. Ferrari D, Villalba M, Chiozzi P, et al. Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol, 1996, 156(28):1531-1539.
11. Lu KT, Wang YW, Yang JT, et al. Effect of interleukin-1 on traumatic brain injury-induced damage to hippocampal neurons. J Neurotrauma, 2005, 22(10):885-895.
12. Johnson VE, Stewart JE, Begbie FD, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain, 2013, 135(34):28-42.
13. Smith DH, Chen XH, Pierce JE, et al. Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma, 1997, 14(5):715-727.
14. Zhu G, Okada M, Yoshida S, et al. Effects of interleukin-1beta on hippocampal glutamate and GABA releases associated with Ca²⁺-induced Ca²⁺ releasing systems. Epilepsy Res, 2006, 71(10):107-116.
15. Vezzani A, Moneta D, Conti M, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA, 2000, 97(16):11534-11539.
16. Ravizza T, Lucas SM, Balosso S, et al. Inactivation of caspase-1 in rodent brain:a novel anticonvulsive strategy. Epilepsia, 2006, 47(16):1160-1168.
17. Rijkers H, Majoie HJ, Hoogland G, et al. The role of interleukin-1 in seizures and epilepsy:a critical review. Exp Neurol, 2009, 216(112):258-271.
18. Darrah SD, Miller MA, Ren D, et al. Genetic variability in glutamic acid decarboxylase genes:associations with post-traumatic seizures after severe TBI. Epilepsy Res, 2013, 103(20):180-194.
19. Wagner AK, Miller MA, Scanlon J, et al. Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI. Epilepsy Res, 2010, 90(11):259-272.
20. Kauffman MA, Moron DG, Consalvo D, et al. Association study between interleukin 1 beta gene and epileptic disorders:a HuGe review and meta-analysis. Genet Med, 2008, 10(5):83-88.
21. Hall SK, Perregaux DG, Gabel CA, et al. Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum, 2004, 50(12):1976-1983.
22. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy:definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 2005, 46(21):470-472.
23. Bratton SL, Bullock RM, Carney N, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma, 2007, 24(6):s 37-44.
24. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, doubleblind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med, 1990, 323(25):497-502.
25. Gennarelli TA, Wodzin E. AIS 2005:a contemporary injury scale. Injury, 2006, 37(11):1083-1091.
26. Baker SP, O'Neill B, Haddon WJr, et al. The injury severity score:a method for describing patients with multiple injuries and evaluating emergency care. J Trauma, 1974, 14(3):187-196.
27. Berry C, Ley EJ, Tillou A, et al. The effect of gender on patients with moderate to severe head injuries. J Trauma, 2009, 67(13):950-953.
28. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 1988, 16(9):1215.
29. Mellergard P, Aneman O, Sjogren F, et al. Differences in cerebral extracellular response of interleukin-1b, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe trauma in humans. Neurosurgery, 2011, 68(21):12-19.
30. Camargo MC, Mera R, Correa P, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer:a meta-analysis. Cancer Epidemiol Biomarkers Prev, 2006, 15(11):1674-1687.
31. National Institute of Neurological Disorders and Stroke. Epilepsy research benchmarks progress report 2007-2012. NINDS Online, 2013, 9(4):1-59.
32. Zou H, Brayer SW, Hurwitz M, et al. Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury. Neurorehabil Neural Repair, 2013, 27:878-888. Epilepsia, 2014, 55(7):1109-1119.
33. Omran A, Peng J, Zhang C, et al. Interleukin-1b and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. Epilepsia, 2012, 53(8):1215-1224.
34. Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol, 2005, 5(2):629-640.
35. Acosta SA, Tajiri N, Shinozuka K, et al. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. Plos One, 2013, 8(2):e53376.
36. Boles J, Goyal A, Kumar R, et al. Chronic inflammation after severe traumatic brain injury:characterization and associations with outcome. Presented at Annual Symposium of the National Neurotrauma Society, 2012, 7(1):22-25.
37. Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuro Inflammation, 2012, 9(3):236.
38. Skinner RA, Gibson RM, Rothwell NJ, et al. Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol, 2009, 156(23):1115-1123.
39. Aibiki M, Maekawa S, Ogura S, et al. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma, 1999, 16(10):225-232.
40. Helmy A, Carpenter KLH, Menon DK, et al. The cytokine response to human traumatic brain injury:temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab, 2011, 31(12):658-670.
41. Lee SC, Liu W, Dickson DW, et al. Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol, 1993, 150(21):2659-2667.
42. Brown R, Li Z, Vriend CY, et al. Suppression of splenic macrophage interleukin-1 secretion following intracerebroventricular injection of interleukin-1 beta:evidence for pituitary-adrenal and sympathetic control. Cell Immunol, 1991, 132(23):84-93.
43. Van der Zee CE, Rashid K, Le K, et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J Neurosci, 1995, 15(7):5316-5323.
44. Spranger M, Lindholm D, Bandtlow C, et al. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system:comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur J Neurosci, 1990, 2(1):69-76.
45. DeKosky ST, Goss JR, Miller PD, et al. Upregulation of nerve growth factor following cortical trauma. Exp Neurol, 1994, 130(60):173-177.
46. DeKosky ST, Styren SD, O'Malley ME, et al. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain. Ann Neurol, 1996, 39(12):123-127.
47. von Wedel-Parlow M, Wolte P, Galla HJ, et al. Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro. J Neurochem, 2009, 111(15):111-118.
48. Pociot F, Mølvig J, Wogensen L, et al. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest, 1992, 22(9):396-402.
49. Santarsieri M, Niyonkuru C, McCullough EH, et al. Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury. J Neurotrauma, 2014, 31(5):699-712.
50. Schmitz G, Kaminski WE, Porsch-Ozcurumez M, et al. ATPbinding cassette transporter A1 (ABCA1) in macrophages:a dual function in inflammation and lipid metabolism. Pathobiology, 1999, 67(11):236-240.
51. Hamon Y, Luciani MF, Becq F, et al. Interleukin-1beta secretion is impaired by inhibitors of the ATP bind cassette transport, ABC1. Blood, 1997, 90(16):2911-2915.
52. Gao WM, Chadha MS, Kline AE, et al. Immunohistochemical analysis of histone H3 acetylation and methylation-evidence for altered epigenetic signaling following traumatic brain injury in immature rats. Brain Res, 2006, 1070(221):31-34.
53. Chen H, Wilkins LM, Aziz N, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet, 2006, 15(7):519-529.
54. Chen X, El Gazzar M, Yoza BK, et al. The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. J Biol Chem, 2009, 284(18):27857-27865.
55. Dominici R, Malferrari G, Mariani C, et al. The Interleukin 1-beta exonic (+3953) polymorphism does not alter in vitro protein secretion. Exp Mol Pathol, 2002, 73(21):139-141.

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白细胞介素-1β与外伤后癫痫发生的联系——一个遗传学和生物标记物的队列研究

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