CYTOKINES & BACK PAIN

Neuromodulation. 2017 Feb 13. doi: 10.1111/ner.12586. [Epub ahead of print]

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain.

Kinfe TM1,2, Muhammad S1, Link C3, Roeske S4, Chaudhry SR1, Yearwood TL5.

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Abstract

OBJECTIVES:

Burst spinal cord stimulation (SCS) has been reported to reduce back pain and improve functional capacity in Failed Back Surgery Syndrome (FBSS). However, its mechanism of action is not completely understood. Systemic circulating cytokines have been associated with the development of chronic back pain.

METHODS:

This prospective, feasibility study enrolled 12 refractory FBSS patients with predominant back pain (70% of overall pain) suitable for Burst SCS. Back and leg pain intensity (back pain [VASB ]/leg pain [VASL ]), functional capacity (sleep quality [PSQI]), depressive symptoms (BDI), body weight, stimulation parameters, and plasma levels of pro-inflammatory (Il-1b; TNF; HMGB1)/anti-inflammatory (Il-10) cytokines were collected at baseline and after three months of Burst SCS and compared to healthy controls.

RESULTS:

Pain intensity (pre VASB : 8.25 ± 0.75 vs. post 1.42 ± 1.24) and functional capacity (PSQI: pre 7.92 ± 3.92 vs. post 3.42 ± 1.24; BDI: pre 20.83 ± 3.56 vs. post 10.92 ± 0.75) significantly improved compared to baseline. Pro-inflammatory HMGB1 remained unchanged (preburst: 3.35 ± 3.25 vs. postburst: 3.78 ± 3.83 ng/mL; p = 0.27; W = -30) versus the HC group (2.53 ± 2.6 ng/mL; p = 0.47; U = 59), while anti-inflammatory IL-10 levels were significantly elevated after burst SCS as compared to baseline (preburst 12.54 ± 22.95 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48) and HC group (HC: 7.03 ± 11.6 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48; p = 0.04). Baseline preburst IL-10 values and preburst VASB significantly correlated (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while correlation was not significant between postburst IL-10 values and postburst VASB (Spearman correlation r = -0.49; p = 0.18; 95 CI -0.83 to -0.15). Postburst IL-10 values correlated significantly with postburst PSQI scores (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while no correlation was found between preburst and postburst changes related to the BDI.

CONCLUSIONS:

Burst SCS increased systemic circulating anti-inflammatory IL-10, improved FBSS back pain and back pain associated co-morbidities like disrupted sleep architecture and depressive symptoms in FBSS patients. Thus, suggesting a possible relationship between burst SCS and burst-evoked modulation of peripheral anti-inflammatory cytokine IL-10 in chronic back pain.

J Transl Med. 2016 Mar 17;14:77. doi: 10.1186/s12967-016-0833-9.

IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells.

Li JK1, Nie L1, Zhao YP1, Zhang YQ1, Wang X2, Wang SS1, Liu Y1, Zhao H1, Cheng L3,4.

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Abstract

BACKGROUND:

Low back pain and sciatica caused by intervertebral disc (IVD) disease are associated with inflammatory responses. The cytokine interleukin 17 (IL-17) is elevated in herniated and degenerated IVD tissues and acts as a regulator of disc inflammation. The objective of this study was to investigate the involvement of IL-17A in IVD inflammatory response and to explore the mechanisms underlying this response.

METHODS:

Cells were isolated from nucleus pulposus (NP) tissues collected from patients undergoing surgeries for IVD degeneration. The concentrations of COX2 and PGE2, as well as of select proteins involved in the mitogen-activated protein kinase (MAPK)/activating protein-1 (AP-1) pathway, were quantified in NP cells after exposure to IL-17 with or without pretreatment with MAPK or AP-1 inhibitors.

RESULTS:

Our results showed that IL-17A increased COX2 expression and PGE2 production via the activation of MAPKs, including p38 kinase and Jun N-terminal kinase (JNK). Moreover, IL-17A-induced COX2 and PGE2 production was shown to rely on p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner.

CONCLUSION:

In summary, our results indicate that IL-17A enhances COX2 expression and PGE2 production via the p38/c-Fos and JNK/c-Jun signalling pathways in NP cells to mediate IVD inflammation.

Med Sci Monit. 2017 Feb 5;23:659-664.

MicroRNA-146a Ameliorates Inflammation via TRAF6/NF-κB Pathway in Intervertebral Disc Cells.

Lv F1,2, Huang Y3, Lv W4, Yang L2, Li F3, Fan J5, Sun J1.

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Abstract

BACKGROUND Intervertebral disc degeneration (IDD) has been widely recognized as a major contributor to low back pain. Accumulating evidence suggests that IDD is linked to various pro-inflammatory cytokines and metabolites. Recently, numerous studies have demonstrated that microRNAs (miRNAs) play a pivotal role in the development of most disorders, including degenerative disc diseases. Previous reports have revealed that miRNA-146a (miR-146a) could attenuate neuropathic pain in the spinal cord. The aim of this study was to investigate the role of miR-146a in the inflammatory response of IDD. MATERIAL AND METHODS Quantitative real-time (RT)-PCR was performed to investigate the levels of miR-146a in the PBMCs (peripheral blood mononuclear cells) of patients with IDD. Human nucleus pulposus (NP) cells were transiently transfected with miR-146a mimic; control NP cell transfections lacked miR-146a. Then all NP cells were treated with LPS (10 μM) to induce inflammation. The mRNA levels of miR-146a in NP cells were determined by RT-PCR. In addition, the mRNA and protein expression levels of tumor necrosis factor (TNF), receptor-associated factor 6 (TRAF6), and nuclear factor (NF)-κB in NP cells were evaluated by quantitative RT-PCR and Western blot analysis, respectively. RESULTS We found that miR-146a was significantly downregulated in the PBMCs of patients. Moreover, overexpression of miR-146a significantly decreased the levels of pro-inflammatory cytokines in LPS-stimulated NP cells. The mRNA and protein levels of TRAF6 and NF-κB were downregulated by miR-146a overexpression. CONCLUSIONS These results suggest that overexpression of miR-146a could promote IDD through the TRAF/NF-κB pathway. Our findings also highlight miR-146a as a novel possible therapeutic target for IDD.

Exp Ther Med. 2016 Dec;12(6):3917-3922. doi: 10.3892/etm.2016.3878. Epub 2016 Nov 7.

Protective effects of resveratrol on autologous nucleus pulposus model of radiculopathy.

Lin B1, Yu H1, He Y1, Xu Y1, Zhang W1, Lu C1, Ao Q1.

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Abstract

Nucleus pulposus (NP) has been suggested to trigger an autoimmune response if exposed to the immune system, which plays a key role in neuropathic pain. Therefore, appropriate suppression of inflammation is a key factor for treating the radiculopathy caused by intervertebral disk (IVD) degeneration. Resveratrol, a key component of red wine, has been suggested to exhibit anti-inflammatory properties in vitro and in vivo. However, the effects of resveratrol on NP-mediated pain in vivo have not been studied. The aim of the present study was to investigate whether resveratrol may be useful in treating NP-mediated pain in an autologous NP model of radiculopathy. A total of 36 adult male Sprague-Dawley rats were allocated randomly into sham (group I), saline-treated (group II) and resveratrol-treated (group III) groups. Animal behavior in response to non-noxious mechanical stimulation with von Frey filaments was compared at days 0 (baseline), 3, 7, 14 and 21 following surgery. The expression of proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) were assessed at days 7 and 14. The data showed that resveratrol exhibited an anti-inflammatory effect on the expression of proinflammatory cytokines. Compared with group II, the expression of TNF-α and IL-1 was significantly decreased at each time point in group III. In addition, resveratrol significantly reduced pain behavior triggered by the application of NP tissue on the dorsal root ganglion for up to 14 days. These data suggest that resveratrol has potential for the treatment of NP-mediated pain, indicating a potential clinical application.

Clin Chem Lab Med. 2017 Jan 11. pii: /j/cclm.ahead-of-print/cclm-2016-0942/cclm-2016-0942.xml. doi: 10.1515/cclm-2016-0942. [Epub ahead of print]

The serum concentrations of leptin and MCP-1 independently predict low back pain duration.

Lippi GDagostino CBuonocore RAloe RBonaguri CFanelli GAllegri M.

Abstract

BACKGROUND:

Low back pain (LBP) is a very frequent condition, affecting most people at some point throughout their life. This cross-sectional study was aimed to investigate a selected panel of cytokines and inflammatory biomarkers in patients with or without LBP.

METHODS:

The study population consisted of 104 patients diagnosed with LBP (52 non-persistent and 52 persistent) and 52 healthy subjects with no LBP. Blood samples were collected for assessment of adiponectin, leptin, monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP). The duration of LBP was categorized as "no pain", "non-persistent LBP" and "persistent LBP".

RESULTS:

Higher values of CRP and lower concentrations of both leptin and MCP-1 were found in LBP patients compared to controls, whereas adiponectin did not differ among groups. MCP-1 was also lower in patients with non-persistent than in those with persistent LBP. Age, leptin (relative risk, 11.8; 95% CI, 3.9-35.8) and MCP-1 (relative risk, 2.7; 95% CI, 1.7-4.4) were independently associated with presence and duration of LBP. The combination of age, leptin and MCP-1 predicted 61% of the risk of LBP duration. The area under the curve of MCP-1 for distinguishing persistent from non-persistent LBP was 0.65 (95% CI, 0.54-0.76).

CONCLUSIONS:

Then results of our study suggest that leptin and MCP-1 may be promising biomarkers for diagnosis of acute LBP and its risk to become chronic.

Oncotarget. 2017 Jan 17;8(3):3781-3797. doi: 10.18632/oncotarget.14389.

Epoxyeicosanoids prevent intervertebral disc degeneration in vitro and in vivo.

Li J1, Guan H1, Liu H1, Zhao L1, Li L2, Zhang Y1, Tan P1, Mi B1, Li F1.

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Abstract

Intervertebral disc (IVD) degeneration is considered a common cause of low back pain. In the degenerating IVD, the production of pro-inflammatory cytokines, including IL-1 and TNF-α, progressively increases, contributing to the degenerative process. Epoxyeicosatrienoic acids (EETs), synthesized from arachidonic acid by cytochrome P450 enzymes, act as autocrine and paracrine effectors in regulating inflammation, cardiovascular functions, and angiogenesis. EETs were shown to be especially potent promoters of tissue regeneration. Considering their anti-inflammatory and anti-catabolic potential, we investigated whether EETs can influence IVD degeneration. We found that 14,15-EET protected rat nucleus pulposus (NP) cells against death induced by treatment with H2O2and TNF-α in vitro. At the molecular level, 14,15-EET significantly inhibited the NF-κB pathway, which plays essential roles in the degeneration and survival of NP cells. As a result, 14,15-EET efficiently prevented the matrix remodeling response of NP cells to TNF-α. Using a needle-punctured rat tail model, the influence of 14,15-EET on IVD degeneration in vivo was evaluated using radiographs, magnetic resonance images (MRI), and histological analysis. We observed that 14,15-EET prevented IVD degeneration. Our findings demonstrated that 14,15-EET can enhance the survival of NP cells and inhibit IVD degeneration. The EET pathway may be a novel therapeutic target against IVD degeneration.

Am J Phys Med Rehabil. 2016 Nov 24. [Epub ahead of print]

Inflammatory Mediators and Pain in the First Year After Acute Episode of Low-Back Pain in Elderly Women: Longitudinal Data from Back Complaints in the Elders-Brazil.

Queiroz BZ1, Pereira DSRosa NMLopes RAAndrade AGFelício DCJardim RMLeopoldino AASilva JPPereira LS.

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Abstract

OBJECTIVE:

The aims of this study were to determine the course of plasma levels of inflammatory mediators (interleukin 6 [IL-6], tumor necrosis factor α [TNF-α], soluble TNF receptor 1 [sTNF-R1]) and the severity of low-back pain (LBP) over 6 to 12 months after an acute episode of LBP in elderly women and to establish an association between inflammatory mediators and LBP recovery.

DESIGN:

This was a longitudinal study of a subsample (155 elderly women with acute LBP, aged ≥65 years) of the international Back Complaints in the Elders cohort study. Plasma levels of IL-6, TNF-α, and sTNF-R1 were measured using enzyme-linked immunosorbent assays and pain severity using the numerical pain scale.

RESULTS:

There was a decrease in the severity of LBP (P = 0.033) and in the levels of IL-6 and TNF-α (P < 0.001) and an increase in sTNF-R1 (P < 0.001) in the first year after an acute episode of LBP. The probability of occurrence of pain relief at the 12-month follow-up was 2.22 times higher in elderly women who had low levels of IL-6 (<1.58 pg/mL) at baseline.

CONCLUSIONS:

Our findings showed a relationship between inflammation and LBP by establishing that low IL-6 plasma levels preceded outcome (LBP recovery), supporting the concept that proinflammatory cytokines promote pain.

Acta Biochim Biophys Sin (Shanghai). 2017 Jan;49(1):1-13. doi: 10.1093/abbs/gmw112. Epub 2016 Nov 17.

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration.

Wang C1, Yu X2, Yan Y1, Yang W3, Zhang S1, Xiang Y3, Zhang J3, Wang W4.

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Abstract

Intervertebral disc (IVD) degeneration (IDD) is the most common cause leading to low back pain (LBP), which is a highly prevalent, costly, and crippling condition worldwide. Current treatments for IDD are limited to treat the symptoms and do not target the pathophysiology. Tumor necrosis factor-α (TNF-α) is one of the most potent pro-inflammatory cytokines and signals through its receptors TNFR1 and TNFR2. TNF-α is highly expressed in degenerative IVD tissues, and it is deeply involved in multiple pathological processes of disc degeneration, including matrix destruction, inflammatory responses, apoptosis, autophagy, and cell proliferation. Importantly, anti-TNF-α therapy has shown promise for mitigating disc degeneration and relieving LBP. In this review, following a brief description of TNF-α signal transduction, we mainly focus on the expression pattern and roles of TNF-α in IDD, and summarize the emerging progress regarding its inhibition as a promising biological therapeutic approach to disc degeneration and associated LBP. A better understanding will help to develop novel TNF-α-centered therapeutic interventions for degenerative disc disease.

Brain Behav Immun. 2017 Feb;60:84-92. doi: 10.1016/j.bbi.2016.10.003. Epub 2016 Oct 6.

Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain.

Klyne DM1, Barbe MF2, Hodges PW3.

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Abstract

Systemic inflammation is linked with development and persistence of many pathological pain states. Although chronic phase inflammatory responses are well reported, the acute phase has received limited attention. Here we investigated circulating pro-inflammatory cytokines and C-reactive protein (CRP), and explored their relationships with symptom severity and other factors in acute low back pain (LBP). Ninety-nine individuals within two weeks of onset of acute LBP and 55 pain-free controls completed questionnaires related to their pain (visual analogue scale, VAS) and disability, behaviour, sleep quality and psychological status. CRP, interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1β (IL-1β) were measured from serum samples. Biomarkers were compared between LBP and control participants, and in a separate analysis, for those with "high-pain" (VAS ⩾4) and "low-pain" (VAS <4). The relationships between biomarkers and all other variables, including other cytokines/CRP were assessed. CRP was higher in LBP than controls and in those with high- than low-pain (p<0.01). IL-6 was higher in those with high- than low-pain (p<0.05), but not controls. Various pain and non-pain factors were associated with each biomarker differently. These findings suggest systemic CRP and IL-6 are important contributors to inflammation in the early post-onset phase of LBP and that various factors can shape these responses.

Spine J. 2017 Jan;17(1):129-134. doi: 10.1016/j.spinee.2016.08.006. Epub 2016 Aug 4.

Are Modic changes associated with intervertebral disc cytokine profiles?

Schroeder GD1, Markova DZ2, Koerner JD3, Rihn JA3, Hilibrand AS3, Vaccaro AR3, Anderson DG3, Kepler CK3.

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Abstract

BACKGROUND CONTEXT:

Degenerative changes including Modic changes (MCs) are commonly observed in patients with chronic low back pain. Although intervertebral disc (IVD) cytokine expression has been shown to be associated with low back pain, the cytokine profile for degenerative IVD with and without MC has not been compared.

PURPOSE:

This study aimed to evaluate the potential association between IVD cytokine expression and MCs.

STUDY DESIGN:

A laboratory study was carried out.

METHODS:

The IVD tissue samples from 10 patients with type II MCs and 10 patients without MCs who underwent an anterior lumbar interbody and fusion for significant low back pain were collected. The expression levels of 42 cytokines were determined using a RayBio Human Cytokine Antibody Array 3 (RayBiotech Inc, Norcross, GA, USA) and the results were verified with enzyme-linked immunosorbent assay (ELISA).

RESULTS:

The cytokine array demonstrated a statistically significant increase in the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) (p=.001) and epithelial-derived neutrophil-activating peptide 78 (ENA-78) (p=.04), and a trend toward an increase in interleukin-1β (IL-1β) (p=.12) and tumor necrosis factor-α (TNF-α) (p=.22) in IVDs associated with type II MCs. These results were validated with ELISA which demonstrated a 3.85-fold increase in the GM-CSF level between IVDs with type II MCs compared with those without MCs (p=.03). Similarly there was a significant increase in the level of both ENA-78 (3.68-fold, p=.02) and IL-1β (2.11-fold, p=.01) in IVDs with type II MCs. Lastly, there was a trend (p=.07) toward an increase in TNF-α in IVDs with type II MCs (4.4-fold).

CONCLUSION:

Intervertebral discs with type II MCs demonstrate a significant increase in IL-1β, GM-CSF, and ENA-78, and there is a trend toward an increase in TNF-α. These results further strengthen the association between MCs and low back pain.

Ann Rheum Dis. 2017 Mar;76(3):576-584. doi: 10.1136/annrheumdis-2016-209428. Epub 2016 Aug 3.

The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration.

Dudek M1,2, Yang N1,2, Ruckshanthi JP1,2, Williams J1,2, Borysiewicz E1, Wang P1, Adamson A1, Li J1, Bateman JF3, White MR1, Boot-Handford RP2, Hoyland JA4,5, Meng QJ1,2.

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Abstract

OBJECTIVES:

The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration.

METHODS:

Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1.

RESULTS:

Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs.

CONCLUSIONS:

We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.

Biosci Rep. 2016 Aug 5;36(4). pii: e00361. doi: 10.1042/BSR20160187. Print 2016 Aug.

Inflammation in low back pain may be detected from the peripheral blood: suggestions for biomarker.

Li Y1, Liu J2, Liu ZZ2, Duan DP2.

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Abstract

Biomarker for prediction of development of low back pain, and disease progression in chronic conditions are virtually non-existent. In the present study, we examined evidence of inflammation in the peripheral blood and demonstrated significant changes in neuroinflammation markers in subjects with chronic low back pain in comparison with control subjects. The present study was performed using peripheral blood from subjects with chronic low back pain and age-matched control subjects. Western blotting, real-time RT-PCR, cell culture and in vitro assays were incorporated to perform the current study. We obtained evidence that the balance between proinflammatory and anti-inflammatory cytokines is misaligned, with decrease in interleukin-10 (IL-10) expression and increase in interleukin-6 (IL-6) expression. Furthermore, we demonstrated increase in CD16 monocyte expression. Cells were cultured under differential conditions to generate M1/M2 macrophages. In the macrophages, opioid secretory capacity was shown to be diminished. Finally, Dragon (repulsive guidance molecule b, RGMb) expression was shown diminished in M1 macrophages, which serves as a key transcriptional inhibitor of IL-6 expression. These biochemical and cellular alterations in chronic low back pain can serve as potential biomarkers for assessing disease initiation, intensity and progression.

Clin Exp Immunol. 2016 Sep;185(3):301-8. doi: 10.1111/cei.12818.

Effect of probiotics on clinical and immune parameters in enthesitis-related arthritis category of juvenile idiopathic arthritis.

Shukla A1, Gaur P1, Aggarwal A1.

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Abstract

Gut microflora and dysbiosis as an environmental factor has been linked to the pathogenesis of enthesitis-related arthritis (JIA-ERA); thus, we performed a proof-of-concept study of probiotics to modulate the gut-flora and study the effects on immune and clinical parameters of children having JIA-ERA. Forty-six children with active JIA-ERA were randomized to placebo or probiotic therapy along with non-steroidal anti-inflammatory drugs (NSAIDs) for 12 weeks. Patients were assessed using a six-point composite disease activity index (mJSpADA) based on morning stiffness, joint count, enthesitis count, sacroiliitis/inflammatory back pain, uveitis and erythrocyte sedimentation rate/C-reactive protein (ESR/CRP). Frequencies of T helper type 1 (Th1), Th2, Th17 and regulatory T cells in blood were measured using flow cytometry. Serum cytokines interferon (IFN)-γ, interleukin (IL)-4, IL-17, IL-10, tumour necrosis factor (TNF)-α and IL-6 were measured by cytokine bead array using flow cytometer.

The average age of 46 children (44 boys) was 15 ± 2.5 years and duration of disease was 3.5 ± 3 years. There was no significant difference in improvement in mJSpADA between the two groups (P = 0·16). Serum IL-6 levels showed a decrease (P < 0·05) in the probiotic-group. Th2 cell frequency (P < 0·05) and serum IL-10 levels (P < 0·01) showed an increase in the placebo group, but again the probiotic use did not show a significant change in immune parameters when compared to the placebo. Adverse effects among the probiotic and placebo groups were diarrhea (36 versus 45%), abdominal pain (9 versus 20%), minor infections (4·5 versus 20%) and flatulence (23 versus 15%), respectively. Thus, we can conclude that probiotic therapy in JIA-ERA children is well tolerated, but failed to show any significant immune or clinical effects over NSAID therapy.

J Med Invest. 2016;63(1-2):1-7. doi: 10.2152/jmi.63.1.

Clinical Significance of High-intensity Zone for Discogenic Low Back Pain: A Review.

Jha SC1, Higashino KSakai TTakata YAbe MYamashita KMorimoto MFukuta SNagamachi ASairyo K.

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Abstract

High-intensity zone (HIZ) was originally described as a high-intensity signal on T2-weighted magnetic resonance (MR) images, located in the posterior annulus fibrosus, clearly separated from the nucleus pulposus. Among symptomatic patients with low back pain, HIZ is present in 28-59% of cases. In morphologically abnormal discs, high sensitivity and specificity of 81% and 79%, respectively, were reported for HIZs and concordant pain during discography. In contrast, another report indicated low rates. Although most papers reported high sensitivity and specificity for this relationship, it remains controversial. Regarding the pathology of HIZs, inflammatory granulation tissues are found at sites showing HIZs. Such inflammatory tissues produce pro-inflammatory cytokines and mediators, which sensitize the nociceptors within the disc and cause pain. An effective treatment for this condition is yet to be established. Recently, minimally invasive surgery using percutaneous endoscopic discectomy (PED) under local anesthesia was introduced. After removal of the degenerated disc material, the HIZ is identified with the endoscope and then coagulated and modulated with a bipolar radio pulse. This technique is called thermal annuloplasty. In conclusion, HIZs is an important sign of painful intervertebral disc disruption, if identified precisely based on factors such as location and intensity.

Spine J. 2016 Jul;16(7):857-61. doi: 10.1016/j.spinee.2016.03.019. Epub 2016 Mar 11.

Cytokine profile in degenerated painful intervertebral disc: variability with respect to duration of symptoms and type of disease.

Altun I1.

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Abstract

BACKGROUND CONTEXT:

Neuroinflammation is supposed to play a crucial role in the generation of chronic pain. Numerous trials have documented the contribution of proinflammatory cytokines in the pathophysiology of pain associated with peripheral and central nociception. Local and systemic expressions of proinflammatory cytokines have been implicated as mediators of pain. Among these cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are especially notable because of their hyperalgesic impacts after nerve damage.

PURPOSE:

The aim of the present study was to evaluate and compare the tissue levels of IL-1β, IL-6, interleukin-10 (IL-10), and TNF-α in subligamentous and free fragment types of degenerated intervertebral disc in acute and chronic periods.

STUDY DESIGN:

This was a cross-sectional study.

PATIENT SAMPLE:

A cross-sectional study was implemented on a total of 49 patients (24 women, 25 men) with an average age of 38.2±4.9 treated surgically by means of microdiscectomy.

OUTCOME MEASURES:

Of these cases, 19 had complaints for less than 6 months, whereas 30 patients had been suffering from low back pain and leg pain for more than 6 months. Thirty-eight patients have been diagnosed with subligamentous type and 11 patients had free fragment type of disc degeneration.

METHODS:

The levels of IL-1β, IL-6, IL-10, and TNF-α were assessed in tissue samples prepared from nucleus pulposus tissue obtained during microdiscectomy. Results were compared in patients with acute and chronic duration of complaints, as well as subligamentous and free fragment types of intervertebral disc degeneration.

RESULTS:

The levels of IL-1β (p<.001), IL-6 (p<.001), IL-10 (p<.001), and TNF-α (p<.001) were significantly higher in patients with acute duration of complaints. Similarly, free fragment type of intervertebral disc degeneration displayed remarkably higher levels of IL-1β (p=.009), IL-6 (p<.001), IL-10 (p=.024), and TNF-α (p=.017) compared with the subligamentous type.

CONCLUSIONS:

Inflammatory cytokines seem to have a more apparent role in intervertebral disc degeneration especially in acute period and in free fragment type. Further trials should be performed for elucidation of pathophysiology at the molecular level and the development of more effective diagnostic and therapeutic measures.

Zhongguo Zhen Jiu. 2015 Nov;35(11):1121-3.

[Impact of huolong moxibustion on TNF-α and pain degree in the patients of discogenic low back pain].

[Article in Chinese]

Yan ZHuang WLi SZhang WHu YLiu Chunjing.

Abstract

OBJECTIVE:

To discuss the impact of huolong moxibustion on pain degree in the patients of discogenic low back pain and the effect mechanism.

METHODS:

Sixty-five patients were randomized into an observation group (33 cases) and a control group (32 cases). In the observation group, huolong moxibustion was applied along the distribution of the Governor Vessel, once a day. In the control group, the routine traction combined with massage therapy was adopted, once a day. In the two groups, the treatment was given 6 times a week, at interval of 1 day. In 3 weeks of treatment, pain score and serum tumor necrosis factor α (TNF-α) level were compared with those before treatment in the two groups.

RESULTS:

Compared with those before treatment, pain score and TNF-α level were reduced significantly after treatment in the two groups (both P < 0.05). The results in the observation group were lower than those in the control group (pain score: 1.95 ± 0.61 vs 2.11 ± 0.61; TNF-α: (1.33 ± 0.30) nmol/L vs (1.55 ± 0.48) nmol/L, (both P < 0.05).

CONCLUSION:

Huolong moxibustion significantly alleviates pain in the patients of discogenic low back pain and its effect mechanism is possibly relevant with TNF-α reducing.

Eur Cell Mater. 2015 Sep 21;30:104-16; discussion 116-7.

Disc in flames: Roles of TNF-α and IL-1β in intervertebral disc degeneration.

Johnson ZI1, Schoepflin ZRChoi HShapiro IMRisbud MV.

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Abstract

The intervertebral disc is an important mechanical structure that allows range of motion of the spinal column. Degeneration of the intervertebral disc--incited by aging, traumatic insult, genetic predisposition, or other factors--is often defined by functional and structural changes in the tissue, including excessive breakdown of the extracellular matrix, increased disc cell senescence and death, as well as compromised biomechanical function of the tissue. Intervertebral disc degeneration is strongly correlated with low back pain, which is a highly prevalent and costly condition, significantly contributing to loss in productivity and health care costs. Disc degeneration is a chronic, progressive condition, and current therapies are limited and often focused on symptomatic pain relief rather than curtailing the progression of the disease. Inflammatory processes exacerbated by cytokines tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are believed to be key mediators of disc degeneration and low back pain. In this review, we describe the contributions of TNF-α and IL-1β to changes seen during disc degeneration at both cellular and tissue level, as well as new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes.