Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration
Abstract
:1. Introduction
2. Pathogenetic Aspect of Inflammation in Intervertebral Disk Degeneration
3. Cytokines Alteration in Intervertebral Disk Degeneration
3.1. Pro-Inflammatory Cytokines
3.1.1. Interleukin 1β
3.1.2. Interleukin 2
3.1.3. Interleukin 8
3.1.4. Interleukin 12
3.1.5. Interleukin 17
3.1.6. Interleukin 18
3.1.7. Tumor Necrosis Factor Alpha
3.1.8. Interferons
3.2. Anti-Inflammatory Cytokines
3.2.1. Interleukin 4
3.2.2. Interleukin 6
3.2.3. Interleukin 10
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Hypothesis | Mechanism | References |
---|---|---|
Genetic | Congenital malformations IVD. Monogenic hereditary differentiated and undifferentiated connective tissue dysplasia. Genetic predisposition to impaired vitamin D metabolism ApaI (rs7975232), etc. Post-translational disorders (expression of zinc finger long non-coding RNA antisense 1). MicroRNAs as factors of degradation, inflammation, apoptosis, autophagy, or regulators of mechanosensory perception. Genetic predisposition to overproduction of pro-inflammatory cytokines, including SNVs of the genes: IL1A (rs1800587, rs2071375), IL1B (rs1143634), IL4 (rs2243250 rs2070874); IL-6 SNV in Exon 5 (rs13006435) other three SNVs of IL-6 (rs1800797, rs1800796, rs1800795, rs13006435). Genetic predisposition to impaired synthesis of IVD components, including genes: ACAN (rs1042631, rs1516797), COL1A1 (rs2075555, rs1007086, rs1800012, etc.), COL9A2 (rs137853213), COL9A3 (rs61734651), COL9A1 (rs696990, rs7533552), COL11A2 (rs1800587, rs1337185, rs1463035, rs2072915, rs9277933, rs2076311), HAPLN1 (rs179851), THBS2 (rs9406328), COMP (rs137852650), CD36 (rs3173798, rs3211892), CILP (rs2033711); ASPN (rs373444, rs13301537), GDF-5 (rs143383), etc. Genetic predisposition to increased oxidative processes in IDD: MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs3025058), MMP9 (rs17576), PARK2 (rs926849), RSMB9 (rs2187689, rs7767277), etc. | [12] [13,14] [15] [16] [17,18] [19,20] [21,22] [21,23] |
Mechanical | Overweight and pathological obesity. Sedentary lifestyle (physical inactivity). Lifting weights, sharp turns, frequent bending, twisting, prolonged static load on the spine. Injury of the vertebral motor segment. | [24,25] [26] [26] [27] |
Metabolic | Smoking. Hypoxia and high hemoglobin levels. Knockout of hypoxia-induced factor (HIF)-1alpha. High cholesterol and hyperlipidemia. Hyperglycemia. Hyperuricemia. Metabolic syndrome; Hypothyroidism. | [28] [28,29] [30] [31,32] [33] [25,34] [25,35] [36] |
Circulation | Imbalance of bone homeostasis and osteoporosis. Violation of the blood supply (spasm of arterioles) of the end plate. Atherosclerosis of the arteries of the vertebral motor segment. Anemia, decompression sickness, Gaucher disease. | [37,38] [39] [32] [40] |
Transport | Slow or insufficient outflow of lactate (acidification of the environment) IVD. | [41,42] |
Oxidative stress | Activation of cathepsins in the acid environment of degenerating IVD. Activation of IVD matrix metalloproteinases. Homocysteine-induced oxidative stress and nucleus pulposus ferroptosis by increasing GPX4 methylation. Hemoglobin and heme-induced ferroptosis. | [43,44] [45,46] [47] [48] |
Inflammatory | Absolute or relative overproduction of pro-inflammatory cytokines. Overexpression of ion channels of the TRP family (TRPV4). Overexpression of cytokine receptors. IL-6-induced ferroptosis. Abnormal activation of NLRP3 inflammasome (intracellular PRR). Adipokine resistin IVD degeneration associated with obesity. | [45,46] [49] [2] [50] [41,51] [24,52] |
Autoimmunal | The APOE gene knockout and overexpression of catabolic cytokines in IVD. Autoimmune IVD degeneration due to FAS ligand hypo-expression. | [32] [53] |
Microbiome | “Dysbacteriosis” (axis microbiome gut/skin/spine). Propionibacterium acnes and Staphylococcus epidermidis. | [54,55] |
Infectional | Propionibacterium acnes, as a sluggish infection of IVD. Staphylococci (1% Staphylococcus epidermidis, 12% Staphylococcus auricularis, 12% Staphylococcus laminis, and 5% others). | [56,57] [58,59] |
Nutritional | Autophagy. Increased nutritional requirements of IVD cells. Inadequate nutritional supply of IVD cells. Vitamin C deficiency in the elderly. Deficiency of proline, hydroxyproline. Vitamin D deficiency. | [60] [61,62] [63] [64] [65] [60,66] |
Theory | Role of Cytokine | References |
---|---|---|
Theory of degradation of structures of the extracellular matrix of intervertebral disc | IL-1β, IL-6, IL-8, IL-17, IL-18, IL-21, IL-23, TNF-α, IFN-γ | [2,20,67,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100] |
Theory of oxidation | IL-1β, IL-6, IL-8, IL-17, IL-18, TNF-α, IFN-γ | [67,69,70,71,76,77,78,90,91,92,101,102,103,104,105,106,107,108] |
Mechanical load theory | IL-1β, IL-6, IL-8, IL-17, TNF-α | [76,109,110,111,112,113,114,115] |
Theory of programmed cell death | IL-1β, IL-6, IL-17, IL-18, TNF-α | [2,69,72,75,76,116,117,118,119,120,121,122,123,124] |
Theory of cell proliferation | IL-1β, IL-17, TNF-α | [76,77,90,117,125,126,127,128,129,130,131] |
Theory of premature aging | IL-1β, IL-6, IL-18, TNF-α | [39,73,74,76,77,124,132,133,134,135] |
Autophagy theory | IL-1β, IL-17, TNF-α, IFN-β1 | [71,72,90,133,136,137,138] |
Theory of angiogenesis and neoinnervation | IL-1β, IL-17, TNF-α | [76,90,139,140,141,142] |
Theory of hypoxia | IL-1β, TNF-α | [76] |
Cell cycle disorder theory | IL-1β, IL-17, TNF-α | [77,143] |
Pro-Inflammatory Cytokines | Anti-Inflammatory Cytokines |
---|---|
Interleukin 1 alpha (IL-1α) Interleukin 1 beta (IL1-β) Interleukin 6 (IL-6) Interleukin 8 (IL-8) Interleukin 11 (IL-11) Interleukin 12 (IL-12) Interleukin 17 (IL-17) Interleukin 18 (IL-18) Interleukin 20 (IL-20) Interleukin 33 (IL-33) Interferon gamma (IFN-γ) Tumor necrosis factor alpha (TNF-α) Transforming growth factor beta (TGF-β) Ciliary neurotrophic factor (CNTF) Granulocytic-macrophage colony-stimulating factor (GM-CSF) Leukemia inhibitory factor (LIF) Oncostatin M (OSM) | Interleukin 1 receptor antagonist (IL-1Ra) Interleukin 4 (IL-4) Interleukin 6 (IL-6) Interleukin 10 (IL-10) Interleukin 11 (IL-11) Interleukin 13 (IL-13) Interleukin-18-binding protein (IL1-8BP) Transforming growth factor beta (TGF-β) |
Cytokine | Gene: OMIM Number | Role in Intervertebral Disk | Clinical Role in IDD | References |
---|---|---|---|---|
IL-1β | IL1B: 147720 | Initiation of inflammatory, oxidative, degenerative, apoptotic cascades. Association with premature aging and cell growth arrest. Over-expression of vascular endothelial growth factor, NGF, and BDNF. | +++ | [67,69,73,75,76,77,102,118,132,141,151] |
IL-2 | IL2: 147680 | Growth factor. Initiation of the inflammatory and degenerative cascade. | + | [155,156] |
IL-8 | CXCL8: 146930 | Increased migration (potent chemokine) of neutrophils, T cells, and monocytes, whose enzymes produce free oxygen radicals. Indirect increase in oxidative stress, which can lead to IVD cell death. Involvement in the pathogenesis of acute neuropathic pain. | + | [85,86,87,88,89,106,107,109,110,111,158] |
IL-12A | IL12A: 161560 | Stimulation of proliferation. Activation and increase in the cytotoxicity of NK cells and T cells. Stimulation of differentiation in Th1. Induction of IFN-γ and TNF-α secretion, synergism with pro-inflammatory cytokines with IL-18. | ++ | [141,144] |
IL-17 | IL17A: 603149 | Initiation of the inflammatory and degenerative cascade. Association with cell growth arrest. Stimulation of angiogenesis. | +++ | [68,72,90,91,92,93,94,96,113,115,165,167,172] |
IL-18 | IL18: 600953 | Initiation of the inflammatory and degenerative cascade (IFN-γ activation). Initiation of the apoptotic and oxidative cascade. Association with premature aging of IVD cells. | +++ | [70,83,105,121,122,123] |
TNF-α | TNF: 191160 | Initiation of inflammatory, apoptotic, oxidation, and degenerative cascades. Association with premature aging and cell growth arrest. Autophagy promoter While TNF-α signaling via TNFR2 is anti-inflammatory and cytoprotective, resulting in the induction of proliferation, differentiation, angiogenesis, and tissue repair. | +++ | [71,74,76,77,79,80,104,116,117,126,127,130,133,135,144] |
IFN-γ | IFNG: 147570 | Initiation of the inflammatory and degenerative cascade in IVD cells. Involvement in the pathogenesis of acute neuropathic pain in IDD. | +++ | [2,156,164,191,192] |
Cytokine | Gene: OMIM Number | Role in Intervertebral Disk | Clinical Role in IDD | References |
---|---|---|---|---|
IL-4 | IL4: 147780 | Initiation of Th differentiation into Th2 lymphocytes. Increased Th2 cytotoxicity. Modulation of the function of macrophage cells. Decreased cytotoxicity. Inhibition of LPS, IFN gamma, and induction of TNF-α, IL-1α pathways of degeneration. Induction of production of IL-1β and TNF-α. Stimulation of IL-6 activation and participation together with it in anti-inflammatory, antioxidant activity. Decreased LPS-induced expression of IL-8, IL-12. | +++ | [157,164,194,195,196,199,200,202,203,205,207] |
IL-6 | IL6: 147620 | A key role in the processes associated with immunity and inflammation. Potentiates the inflammatory, degenerative and oxidative cascade. May act as an anti-inflammatory cytokine. Able to stimulate osteoclasts and bone resorption. Suppresses H2O2-associated premature aging and apoptosis. | +++ | [2,32,97,98,99,100,104,108,114,124,157,210,212,213,215] |
IL-10 | IL10: 124092 | Initiation of cellular effects through canonical JAK/STAT, which includes JAK1 and STAT3. Induction of expression of genes associated with immunosuppression. Providing antigens and enhancing immune tolerance. Anti-inflammatory, anti-catabolic, and anti-apoptotic action. Decreased production of IL-1α, IL-1β, IL-6, IL-8, IL-12, TNF-α, IFN-γ, GM-GSF and GCSF. | +++ | [104,224,225,227,228,229,230,231,235,236] |
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Shnayder, N.A.; Ashhotov, A.V.; Trefilova, V.V.; Nurgaliev, Z.A.; Novitsky, M.A.; Vaiman, E.E.; Petrova, M.M.; Nasyrova, R.F. Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration. Int. J. Mol. Sci. 2023, 24, 2360. https://doi.org/10.3390/ijms24032360
Shnayder NA, Ashhotov AV, Trefilova VV, Nurgaliev ZA, Novitsky MA, Vaiman EE, Petrova MM, Nasyrova RF. Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration. International Journal of Molecular Sciences. 2023; 24(3):2360. https://doi.org/10.3390/ijms24032360
Chicago/Turabian StyleShnayder, Natalia A., Azamat V. Ashhotov, Vera V. Trefilova, Zaitun A. Nurgaliev, Maxim A. Novitsky, Elena E. Vaiman, Marina M. Petrova, and Regina F. Nasyrova. 2023. "Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration" International Journal of Molecular Sciences 24, no. 3: 2360. https://doi.org/10.3390/ijms24032360