Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases

Weber et al. Arthritis Research & Therapy (2016) 18:3 DOI 10.1186/s13075-015-0887-8 RESEARCH ARTICLE Open Access Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases Kathryn T. Weber1, D. Olivier Alipui1, Cristina P. Sison1,2,6, Ona Bloom1,2,3, Shaheda Quraishi3,4, M. Chris Overby4, Mitchell Levine4 and Nadeen O. Chahine1,2,4,5* Abstract Background: Many intervertebral disc diseases cause low back pain (LBP). Proinflammatory cytokines and matrix metalloproteinases (MMPs) participate in disc pathology. In this study, we examined levels of serum cytokines and MMPs in human subjects with diagnoses of disc herniation (DH), spinal stenosis (SS), or degenerative disc disease (DDD) relative to levels in control subjects. Comparison between subjects with DH and those with other diagnoses (Other Dx, grouped from SS and DDD) was performed to elaborate a pathological mechanism based on circulating cytokine levels. Methods: Study participants were recruited from a spine neurosurgery practice (n = 80), a back pain management practice (n = 27), or a control cohort (n = 26). Serum samples were collected before treatment and were assayed by multiplex assays for levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ, tumor necrosis factorα, MMP-1, MMP-3, and MMP-9. Inflammatory and degradative mediator levels were compared for subjects with LBP and control subjects, by diagnosis and by treatment groups, controlling for effects of sex, age, and reported history of osteoarthritis. Spearman’s correlation coefficient was used to examine relationships with age, body mass index (BMI), symptom duration, and smoking history. Results: Serum levels of IL-6 were significantly higher in subjects with LBP compared with control subjects. Participants with LBP due to Other Dx had significantly higher levels of IL-6 than DH and controls. Serum levels of MMP-1 were significantly lower in LBP subjects, specifically those with DH, than in control subjects. Positive correlations were found between IL-6 levels and BMI, symptom duration, and age. MMP-1 levels were positively correlated with age. Conclusions: The findings of the present clinical study are the results of the first examination of circulating cytokine levels in DDD and SS and provide evidence for a more extensive role of IL-6 in disc diseases, where patients with DDD or SS have higher serum cytokine levels than those with DH or control subjects. These findings suggest that LBP subjects have low-grade systemic inflammation, and biochemical profiling of circulating cytokines may assist in refining personalized diagnoses of disc diseases. Keywords: Intervertebral disc, Back pain, Inflammatory cytokines, Matrix metalloproteinase, Biomarkers, Disc herniation, Spinal stenosis, Degenerative disc disease, Clinical research, Epidural steroid injections * Correspondence: 1 The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY, USA 2 Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA Full list of author information is available at the end of the article © 2016 Weber et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Weber et al. Arthritis Research & Therapy (2016) 18:3 Background Back pain causes a significant burden on both the healthcare system and the economy. As the second most common cause of physician visits in the United States, low back pain (LBP) contributes an estimated $50 billion to 100 billion in direct healthcare spending [1–4]. Affecting an estimated 40–80 % of people at any point during their lifetime, LBP is a leading cause of disability worldwide [5]. Clinically, LBP is a complicated amalgam of multiple diseases with an unpredictable response to treatment. LBP is caused by multiple triggers with similar clinical presentation, and physical examination is rarely diagnostic. Some of the most common diagnoses for LBP include intervertebral disc herniation (DH), spinal stenosis (SS), and degenerative disc disease (DDD). The intervertebral disc (IVD) is the load-bearing tissue between the vertebral bodies of the spine. The disc is composed of a gelatinous nucleus pulposus (NP) in the center surrounded by a fibrous annulus fibrosis (AF) tissue in the periphery. DH is the focal displacement of disc material beyond the limits of the IVD disc space [6]. DH can irritate nearby nerves and result in pain, numbness, or weakness in the legs. SS is a pathologic narrowing of the spinal canal due to hypertrophy of the ligamentum flavum and is associated with paresthesia, pain, and symptoms of neurologic compromise [7, 8]. DDD includes disc pathology such as desiccation and loss of disc height, diffuse disc bulging, fissures, osteophytes, or endplate sclerosis without meeting a specific indication for herniation or stenosis [6]. Currently, the best prognostic indicators for LBP are based on the underlying diagnosis. In some cases, DH will remodel spontaneously with nonoperative treatment and patients will experience resolution of painful symptoms [9]. In contrast, age is a primary risk factor for SS [10], so people who develop it at younger ages have longer durations of symptoms and worse prognoses [11]. Disruption of the extracellular matrix (ECM) of the disc, such as loss of proteoglycans (PGs) in the NP, increase in degenerative fibrillation in NP and AF, and loss of water content in the NP, are hallmarks of IVD degeneration [12–16]. This has previously been shown to be associated with upregulation of matrix metalloproteinases (MMPs) such as MMP-1, MMP-3, MMP-7, and MMP-13 expression and activity, whose levels correlate with increasing degenerative severity [17–20]. Other catabolic proteases, such as a disintegrin and metalloprotease with thrombospondin motifs (known as ADAMTS), high temperature requirement serine protease A1, and cathepsins, also promote aggrecan turnover and degenerative changes in the disc [21–26]. The increased catabolism of aggrecan is a principal pathological process that leads to degeneration [27], compromising functional integrity of the IVD. Several etiological Page 2 of 14 factors serve as primary initiating events that lead to the abnormal production of catabolic molecules by IVD cells [28]. These factors include aging, genetic predisposition, smoking, infection, abnormal biomech (...truncated)