International Journal of Frontiers in Medicine, 2023, 5(2); doi: 10.25236/IJFM.2023.050210.
Xinyu Li1, Weiren Wang2
1Shanxi Medical University, Taiyuan, 030001, China
2China Medical University, Shenyang, 110000, China
BACKGROUND: Alzheimer's disease (AD) is a common degenerative disease of the central nervous system in the elderly. Several reports have described the serum levels of interleukin (IL-6) in AD. In order to elucidate the status of IL-6 in AD, the article conducted a meta-analysis of previously published results to assess the levels of IL-6 from different tissue sources in AD. METHODS: The levels of Th17 related cytokines (IL-6) in peripheral blood or cerebrospinal fluid (CSF) of AD were systematically reported in domestic and foreign databases. The article assessed pooled data using a random-effects model.The I-square index (I2) was used to assess inconsistency and publication bias was assessed by examining funnel plot asymmetry using the Begg and Egger test. Results: Among 1348 identified studies, the article selected 45 studies for analysis, 36 to investigate IL-6 levels in peripheral blood and 9 to investigate IL-6 levels in CSF of AD versus healthy controls (HCs). The analysis revealed that IL-6 content in peripheral blood of AD was significantly higher than that of HCs[SMD = 0.913, 95% CI (0.345, 1.481), P < 0.05], while the level of IL-6 in CSF showed no statistical significance [SMD = 0.132, 95% CI (-0.579, 0.843), P > 0.05] and could not be used as a marker in AD. CONCLUSIONS: In AD, the level of IL-6, a relevant marker, is increased, and spontaneous IL-6 production by peripheral blood mononuclear cells may be a marker of future AD risk in the elderly, and these data strengthen evidence of the pathophysiological role of inflammation in the development of clinical AD, but suggest that the mechanism of IL-6 action still needs more research and can be used as a potential target to address the problem of AD in the future.
Alzheimer's disease; IL-6; plasma; CSF; meta-analysis
Xinyu Li, Weiren Wang. Levels of IL-6 in peripheral blood and cerebrospinal fluid of Alzheimer's disease: a meta-analysis. International Journal of Frontiers in Medicine (2023), Vol. 5, Issue 2: 53-60. https://doi.org/10.25236/IJFM.2023.050210.
[1] Duong T, Nikolaeva M, Acton P J. C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease. [J]. Brain Research, 1997, 749(1):152-156.
[2] Benveniste EN. Cytokine actions in the central nervous system. Cytokine Growth Factor Rev. 1998 Sep-Dec;9(3-4):259-75. doi: 10.1016/s1359-6101(98)00015-x. PMID: 9918124.
[3] Peng Y, Chen B, Chi L, Zhou Q, Shi Z; Alzheimer’s Disease Neuroimaging Initiative. Patterns of CSF Inflammatory Markers in Non-demented Older People: A Cluster Analysis. Front Aging Neurosci. 2020 Oct 6; 12: 577685. doi: 10.3389/fnagi.2020.577685. PMID: 33132899; PMCID: PMC7573280.
[4] Kaplin A, Carroll KA, Cheng J, Allie R, Lyketsos CG, Calabresi P, Rosenberg PB. IL-6 release by LPS-stimulated peripheral blood mononuclear cells as a potential biomarker in Alzheimer's disease. Int Psychogeriatr. 2009 Apr;21(2):413-4. doi: 10.1017/S1041610208008107. Epub 2008 Dec 1. PMID: 19040786; PMCID: PMC2664968.
[5] Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993; 54: 1-78. doi: 10.1016/s0065-2776(08)60532-5. PMID: 8379461.
[6] Bongioanni P, Boccardi B, Borgna M, Rossi B. T-lymphocyte interleukin 6 receptor binding in patients with dementia of Alzheimer type. Arch Neurol. 1998 Oct;55(10):1305-8. doi: 10.1001/archneur.55.10.1305. PMID: 9779657.
[7] Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett. 1995 Dec 29;202(1-2):17-20. doi: 10.1016/0304-3940(95)12192-7. PMID: 8787820.
[8] Yamada K, Kono K, Umegaki H, Yamada K, Iguchi A, Fukatsu T, Nakashima N, Nishiwaki H, Shimada Y, Sugita Y, et al. Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia. Neurosci Lett. 1995 Feb 17;186(2-3):219-21. doi: 10. 1016/ 0304- 3940(95)11318-q. PMID: 7777201.
[9] Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, Nakajima K, Pyun KH, Kishimoto T. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U S A. 1985 Aug;82(16):5490-4. doi: 10.1073/pnas.82.16.5490. PMID: 2410927; PMCID: PMC391148.
[10] Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 1989 Apr;19(4):689-94. doi: 10.1002/eji.1830190418. PMID: 2543584.
[11] Benveniste EN, Sparacio SM, Norris JG, Grenett HE, Fuller GM. Induction and regulation of interleukin-6 gene expression in rat astrocytes. J Neuroimmunol. 1990 Dec;30(2-3):201-12. doi: 10.1016/0165-5728(90)90104-u. PMID: 2121800.
[12] Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial -derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014 Apr 15;129(15):1586-97. doi: 10. 1161/ CIRCULATION AHA. 113.007469. Epub 2014 Jan 30. PMID: 24481949.
[13] Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry. 2010 Nov 15;68(10):930-41. doi: 10. 1016 /j. biopsych. 2010. 06.012. Epub 2010 Aug 8. PMID: 20692646.
[14] Oh JW, Van Wagoner NJ, Rose-John S, Benveniste EN. Role of IL-6 and the soluble IL-6 receptor in inhibition of VCAM-1 gene expression. J Immunol. 1998 Nov 1;161(9):4992-9. PMID: 9794436.
[15] Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. doi: 10.1038/s 41591- 018-0297-y. Epub 2019 Jan 14. PMID: 30643288; PMCID: PMC6367058.
[16] Singh-Manoux A, Dugravot A, Brunner E, Kumari M, Shipley M, Elbaz A, Kivimaki M. Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife. Neurology. 2014 Aug 5;83(6):486-93. doi: 10.1212/WNL.0000000000000665. Epub 2014 Jul 2. PMID: 24991031; PMCID: PMC4141998.