Increased levels of interleukin 31 (IL-31) in osteoporosis

Ginaldi et al. BMC Immunology (2015) 16:60 DOI 10.1186/s12865-015-0125-9 RESEARCH ARTICLE Open Access Increased levels of interleukin 31 (IL-31) in osteoporosis Lia Ginaldi1, Massimo De Martinis1*, Fedra Ciccarelli1, Salvatore Saitta2, Selene Imbesi2, Carmen Mannucci2 and Sebastiano Gangemi2 Abstract Background: Several inflammatory cytokines play a key part in the induction of osteoporosis. Until now, involvement of the Th2 cytokine interleukin-31 (IL-31) in osteoporosis hadn’t yet been studied. IL-31 is a proinflammatory cytokine mediating multiple immune functions, whose involvement in a wide range of diseases, such as atopic dermatitis, inflammatory bowel diseases and cutaneous lymphomas, is now emerging. Given the important role of IL-31 in inflammation, we measured its serum levels in postmenopausal osteoporotic patients. Methods and results: In fifty-six postmenopausal females with osteoporosis and 26 healthy controls, bone mineral density (BMD) measurements were performed by using calcaneal quantitative ultrasound (QUS) technique, confirmed at the lumbar spine and hip by dual energy X-ray absorptiometry (DXA). Both patients and controls were divided according to age (less or more than 65 years) and disease severity (T-score levels and presence of fractures). Serum IL-31 levels were measured by ELISA technique. Osteoporotic patients exhibited elevated levels of serum IL-31 compared with healthy controls (43.12 ± 6.97 vs 29.58 ± 6.09 pg/ml; p < 0.049). IL-31 expression was higher in over 65 years old patients compared to age-matched controls (45 ± 11.05 vs. 17.92 ± 5.92; p < 0.01), whereas in younger subjects no statistically significant differences were detected between patients and controls (37.91 ± 6.9 vs 32.08 ± 8.2). No statistically significant differences were found between IL-31 levels in patients affected by mild (T-score > -3) compared to severe (T-score < -3) osteoporosis (59.17 ± 9.22 vs 37.91 ± 10.52), neither between fractured and unfractured osteoporotic women (33.75 ± 9.16 vs 51.25 ± 8.9). Conclusions: We showed for the first time an increase of IL-31 serum levels in postmenopausal women with decreased BMD. Although they did not reflect the severity of osteoporosis and/or the presence of fractures, they clearly correlated with age, as reflected by the higher levels of this cytokine in aged patients. Keywords: Osteoporosis, Aging, IL-31, Inflammation, Translational medicine Background In the last few years, many studies have been conducted to understand the processes that regulate physiological and pathological bone turnover and there was increasing evidence of a relationship between the immune system and bone [1, 2]. There is a mutual influence between the immune system and bone tissue cells, mediated by shared receptors, soluble molecules and signalling pathways [3]. T cells have been recognized as key regulators of osteoclast and osteoblast activity in different diseases able to induce osteoporosis, such as rheumatic diseases, * Correspondence: 1 Department of Life, Health, & Environmental Sciences, University of L’Aquila, L’Aquila, Italy Full list of author information is available at the end of the article bone metastasis, periodontitis and chronic infections [4–6]. Also paraphysiological conditions, such as aging and menopause, are associated to dysregulation of bone remodelling leading to loss of bone mass and consequentely, to a state of full-blown osteoporosis [7–9]. Osteoporosis is a systemic skeletal disease characterized by decreased bone mass and microarchitectural deterioration of bone tissue. An excessive bone resorption and/or an inadequate bone formation results in a subsequent increase in bone fragility and susceptibility to fractures [10]. The main regulator of osteoclast differentiation is the receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL), a factor produced by osteoblasts/stromal cells and belonging to the tumour necrosis factor (TNF) family. In the presence of the growth © 2015 Ginaldi 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. Ginaldi et al. BMC Immunology (2015) 16:60 factor M-CSF (macrophage-colony stimulating factor), the activation of its receptor RANK on the surface of osteoclast precursors and mature osteoclasts represents an essential signal for osteoclast differentiation and activation and consequentely bone resorption [11]. Interestingly, immune cells, mainly activated T lymphocytes and antigen presenting cells, can also express RANKL, therefore influencing bone remodelling, both directely and through cytokine production [12]. For example, IL6, IL-17, TNF-α and IFN-γ promote bone loss by favouring osteoclast production and inhibiting osteoblast differentiation [13, 14]. Other cytokines, such as IL-4, IL-12 and IL-33, are strong suppressors of osteoclast differentiation and inhibit bone loss [15, 16]. In addition, many of these cytokines have pleiotropic functions and their role in bone remodelling is cell-type and concentration-dependent and also influenced by the variable cytokine network involved in different physiological and pathological conditions [3]. Interleukin-31 (IL-31) is a cytokine known for almost a decade, belonging to the gp130/IL-6 cytokine family [17] and preferentially expressed by activated memory CD45RO+ T lymphocytes skewed toward a Th2 phenotype [18–22]. Elucidation of the biological activities of IL-31 has only just begun and a biological role of IL-31 in immunity and inflammation is now emerging [18, 19]. It has been observed that this cytokine plays a predominant function in the mediation of inflammatory and lymphoma-associated itch [23], and a secondary one in the suppression of ongoing TH2 responses [17]. IL-31 signals through a heteromeric receptor complex composed of the IL-31 receptor alpha (IL-31RA) and the oncostatin M receptor beta (OSMR) subunits [20]. High receptor expression levels have been found in tissues involved in reproduction, in progenitor cells of myelomonocytic lineage, spleen, thymus, in addition to skin, lung, gut and other tissues [17, 20, 23, 24]. IL31RA is also expressed by a small subpopulation of neurons, representing a critical neuro-immune link between Th2 cells and sensory nerves for the generation of immune-mediated itch [25]. The broad spectrum of its receptor expression on immune- and non-immune cells, suggests that this novel cytokine may have multiple, pleiotropic physiological functions, (...truncated)