Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration

Xiao Deng, Feng Zhao, Baolin Kang, Xin Zhang, Xiao Deng, Feng Zhao, Baolin Kang, Xin Zhang

Abstract

The present study aimed to investigate whether serum interleukin-6 (IL-6) expression levels were associated with the onset and progression of intervertebral disc degeneration (IDD). A comprehensive meta-analysis of the scientific literature from numerous electronic databases was performed, in order to obtain published studies associated with the topic of interest. Relevant case-control studies that had previously assessed a correlation between IL-6 expression levels and IDD were identified using predetermined inclusion and exclusion criteria. The STATA version 12.0 software was used for statistical analysis of the extracted data. A total of 112 studies were initially retrieved, with eight studies meeting the inclusion criteria. These contained a total of 392 subjects, of which 263 were patients with IDD and 129 were healthy controls. A meta-analysis of the eight studies demonstrated that serum IL-6 protein expression levels may be associated with IDD, and this was irrespective of IDD subtype (bulging, protrusion, or sequestration). Notably, serum expression levels of the IL-6 protein were upregulated in intervertebral disc (IVD) protrusion tissue, as compared with normal IVD tissue; thus suggesting that IL-6 may have an important role in the pathophysiological process of IDD.

Keywords: interleukin-6; intervertebral disc; intervertebral disc degeneration; meta-analysis.

Figures

Figure 1.
Figure 1.
A flow chart of the screening process for included studies, and the exclusion criteria, based on the PRISMA guidelines (http://www.prisma-statement.org/). A total of eight case-control studies were included in the present meta-analysis.
Figure 2.
Figure 2.
Methodological quality assessments for each of the included case-control studies using the Critical Appraisal Skill Program (CASP) score. The studies appearing in the figure correspond to references 24–31 (from top to bottom). +, low risk; ?, unidentified risk; –, high risk.
Figure 3.
Figure 3.
Forest plots depicting the correlation between the serum interleukin-6 (IL-6) protein expression levels and (A) intervertebral disc degeneration (IDD), and the (B) bulging; (C) protrusion; and (D) sequestration IDD subtypes. SMD, standardized mean difference; 95% CI, 95% confidence interval.
Figure 4.
Figure 4.
Sensitivity analyses of the correlations between the serum interleukin-6 (IL-6) protein expression levels and intervertebral disc degeneration.. CI, 95% confidence interval; SMD, standardized mean difference.
Figure 5.
Figure 5.
Sensitivity analyses of the correlations between the serum interleukin-6 (IL-6) protein expression levels and the various intervertebral disc degeneration (IDD) subtypes: (A) Bulging, (B) protrusion and (C) sequestered IDD subtypes.
Figure 6.
Figure 6.
Meta-regression analyses of the correlations between the serum interleukin-6 protein expression levels and the various intervertebral disc degeneration subtypes. The results suggested that the heterogeneity was independent of (A) the year of submission, (B) the sample size, (C) the country of submission, and (D) the language of the study. SMD, standardized mean difference.

References

    1. Wang HQ, Yu XD, Liu ZH, Cheng X, Samartzis D, Jia LT, Wu SX, Huang J, Chen J, Luo ZJ. Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3. J Pathol. 2011;225:232–242. doi: 10.1002/path.2931.
    1. Lee JM, Song JY, Baek M, Jung HY, Kang H, Han IB, Kwon YD, Shin DE. Interleukin-1β induces angiogenesis and innervation in human intervertebral disc degeneration. J Orthop Res. 2011;29:265–269. doi: 10.1002/jor.21210.
    1. Siemionow K, An H, Masuda K, Andersson G, Cs-Szabo G. The effects of age, sex, ethnicity, and spinal level on the rate of intervertebral disc degeneration: A review of 1712 intervertebral discs. Spine (Phila Pa) 2011;36:1333–1339. doi: 10.1097/BRS.0b013e3181f2a177.
    1. Akhatib B, Onnerfjord P, Gawri R, Ouellet J, Jarzem P, Heinegård D, Mort J, Roughley P, Haglund L. Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging. J Biol Chem. 2013;288:19280–19287. doi: 10.1074/jbc.M112.443010.
    1. Phillips KL, Jordan-Mahy N, Nicklin MJ, Le Maitre CL. Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann Rheum Dis. 2013;72:1860–1867. doi: 10.1136/annrheumdis-2012-202266.
    1. Hughes SP, Freemont AJ, Hukins DW, McGregor AH, Roberts S. The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain. J Bone Joint Surg Br. 2012;94:1298–1304. doi: 10.1302/0301-620X.94B10.28986.
    1. Adams MA, Dolan P. Intervertebral disc degeneration: Evidence for two distinct phenotypes. J Anat. 2012;221:497–506. doi: 10.1111/j.1469-7580.2012.01551.x.
    1. Huang M, Wang HQ, Zhang Q, Yan XD, Hao M, Luo ZJ. Alterations of ADAMTSs and TIMP-3 in human nucleus pulposus cells subjected to compressive load: Implications in the pathogenesis of human intervertebral disc degeneration. J Orthop Res. 2012;30:267–273. doi: 10.1002/jor.21507.
    1. Erwin WM, Islam D, Inman RD, Fehlings MG, Tsui FW. Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: Implications for the mechanisms of intervertebral disc degeneration. Arthritis Res Ther. 2011;13:R215. doi: 10.1186/ar3548.
    1. Mwale F, Masuda K, Pichika R, Epure LM, Yoshikawa T, Hemmad A, Roughley PJ, Antoniou J. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis Res Ther. 2011;13:R120. doi: 10.1186/ar3423.
    1. Miyagi M, Ishikawa T, Orita S, Eguchi Y, Kamoda H, Arai G, Suzuki M, Inoue G, Aoki Y, Toyone T, et al. Disk injury in rats produces persistent increases in pain-related neuropeptides in dorsal root ganglia and spinal cord glia but only transient increases in inflammatory mediators: Pathomechanism of chronic diskogenic low back pain. Spine (Phila Pa) 2011;36:2260–2266. doi: 10.1097/BRS.0b013e31820e68c7.
    1. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986;324:73–76. doi: 10.1038/324073a0.
    1. Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev. 2011;22:83–89. doi: 10.1016/j.cytogfr.2011.02.003.
    1. Ataie-Kachoie P, Pourgholami MH, Morris DL. Inhibition of the IL-6 signaling pathway: A strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev. 2013;24:163–173. doi: 10.1016/j.cytogfr.2012.09.001.
    1. Yao J, Feng XW, Yu XB, Xie HY, Zhu LX, Yang Z, Wei BJ, Zheng SS, Zhou L. Recipient IL-6-572C/G genotype is associated with reduced incidence of acute rejection following liver transplantation. J Int Med Res. 2013;41:356–364. doi: 10.1177/0300060513477264.
    1. Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer. 2008;44:937–945. doi: 10.1016/j.ejca.2008.02.047.
    1. Studer RK, Vo N, Sowa G, Ondeck C, Kang J. Human nucleus pulposus cells react to IL-6: Independent actions and amplification of response to IL-1 and TNF-α. Spine (Phila Pa 1976) 2011;36:593–599. doi: 10.1097/BRS.0b013e3181da38d5.
    1. Huang KY, Lin RM, Chen WY, Lee CL, Yan JJ, Chang MS. IL-20 may contribute to the pathogenesis of human intervertebral disc herniation. Spine (Phila Pa 1976) 2008;33:2034–2040. doi: 10.1097/BRS.0b013e31817eb872.
    1. Hamamoto H, Miyamoto H, Doita M, Takada T, Nishida K, Kurosaka M. Capability of nondegenerated and degenerated discs in producing inflammatory agents with or without macrophage interaction. Spine (Phila Pa 1976) 2012;37:161–167. doi: 10.1097/BRS.0b013e31821a874b.
    1. Liu Z, Tang NL, Cao XB, Liu WJ, Qiu XS, Cheng JC, Qiu Y. Lack of association between the promoter polymorphisms of MMP-3 and IL-6 genes and adolescent idiopathic scoliosis: A case-control study in a Chinese Han population. Spine (Phila Pa 1976) 2010;35:1701–1705. doi: 10.1097/BRS.0b013e3181c6ba13.
    1. Jackson D, White IR, Riley RD. Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med. 2012;31:3805–3820. doi: 10.1002/sim.5453.
    1. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676–680. doi: 10.1001/jama.295.6.676.
    1. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–137. doi: 10.1002/gepi.20048.
    1. Ouyang B, Su JC, Zeng YD, Bao J. Expression and significance of IL-6, IL-10 and MCP-1 in degenerate human lumbar intervertebral disc tissues. Hainan Yixueyuan Xuebao. 2014;3:381–383. (In Chinese)
    1. Ding GL, Li XY, Lv MX. Expression and clinical study of IL-1 and IL-6 in lumbar disc herniation. Chongqing Yixue. 2014;43:1919–1922. (In Chinese)
    1. Li H. Expression and significance of protrusion of intervertebral disc degeneration in patients with lumbar disc tissue in IL-6, IL-8, TNF-alpha. Shangdong Yixue. 2010;50:65–66. (In Chinese)
    1. Kraychete DC, Sakata RK, Issy AM, Bacellar O, Santos-Jesus R, Carvalho EM. Serum cytokine levels in patients with chronic low back pain due to herniated disc: Analytical cross-sectional study. Sao Paulo Med J. 2010;128:259–262. doi: 10.1590/S1516-31802010000500003.
    1. Song YZ, Deng XZ. Detection and significance of lumbar intervertebral disc nucleus pulposus tissue TNF-alpha, IL-1, IL-6. Shangdong Yixue. 2009;49:87–88. (In Chinese)
    1. Demircan MN, Asir A, Cetinkal A, Gedik N, Kutlay AM, Colak A, Kurtar S, Simsek H. Is there any relationship between proinflammatory mediator levels in disc material and myelopathy with cervical disc herniation and spondylosis? A non-randomized, prospective clinical study. Eur Spine J. 2007;16:983–986. doi: 10.1007/s00586-007-0374-2.
    1. Dong GH, Huang JQ, Cai XJ, Han JH, Xia BJ. Expression of IL-1 and IL-6 in the herniated lumbar disc tissues. Zhongguo Yishi Zazhi. 2004;6:1134–1135. (In Chinese)
    1. Specchia N, Pagnotta A, Toesca A, Greco F. Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J. 2002;11:145–151. doi: 10.1007/s00586-001-0361-y.
    1. Wilke HJ, Urban J, Kümin M. The benefits of multi-disciplinary research on intervertebral disc degeneration. Eur Spine J. 2014;23(Suppl 3):S303–S304. doi: 10.1007/s00586-014-3287-x.
    1. Sakai D, Nakamura Y, Nakai T, Mishima T, Kato S, Grad S, Alini M, Risbud MV, Chan D, Cheah KS, et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun. 2012;3:1264. doi: 10.1038/ncomms2226.
    1. Kalichman L, Hunter DJ. The genetics of intervertebral disc degeneration. Associated genes. Joint Bone Spine. 2008;75:388–396. doi: 10.1016/j.jbspin.2007.11.003.
    1. Holm S, Mackiewicz Z, Holm AK, Konttinen YT, Kouri VP, Indahl A, Salo J. Pro-inflammatory, pleiotropic, and anti-inflammatory TNF-alpha, IL-6, and IL-10 in experimental porcine intervertebral disk degeneration. Vet Pathol. 2009;46:1292–1300. doi: 10.1354/vp.07-VP-0179-K-FL.

Source: PubMed

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