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Levels of Chemerin and Interleukin 8 in the Synovial Fluid of Patients with Inflammatory Arthritides and Osteoarthritis E

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Levels of Chemerin and Interleukin 8 in the Synovial Fluid of Patients with Inflammatory Arthritides and Osteoarthritis E Levels of chemerin and interleukin 8 in the synovial fluid of patients with inflammatory arthritides and osteoarthritis E. Valcamonica1,2, C.B. Chighizola3,4, D. Comi1, O. De Lucia1, L. Pisoni1, A. Murgo1, V. Salvi5, S. Sozzani5,6, P.L. Meroni1,3,4 1Division of Rheumatology, Istituto G. Pini, Milan, Italy; 2Doctorate Course in Genetics, Oncology and Clinical Medicine, University of Siena, Siena, Italy; 3Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 4Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, Milan, Italy: 5Department of Molecular and Translation Medicine, University of Brescia, Brescia, Italy; 6Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Abstract Objective Chemerin and interleukin (IL)-8 are pro-inflammatory mediators whose role in joint inflammation and cartilage degradation has been demonstrated in in-vitro findings. Studies on their presence in synovial fluid (SF) samples may offer further information on their pathogenic role. The aim of this study was to investigate SF chemerin and IL-8 levels in patients with different joint diseases. Methods 37 patients were enrolled: 18 with rheumatoid arthritis (RA), 8 with psoriatic arthritis (PsA) and 11 with osteoarthritis (OA). 41 SF samples were obtained by arthrocentesis in case of knee synovitis. Serum samples were obtained from 13 patients (4 with RA, 6 with PsA and 3 with OA) at the time of arthrocentesis. Chemerin, IL-8, TNF-α and IL-6 levels were measured using commercially available ELISA kits. Immunohistochemical analysis of synovial RA specimens was also performed. Results No difference in chemerin SF levels emerged between patients with immune-mediated inflammatory arthritides and those with OA (p=0.0656), while subjects with inflammatory arthritis displayed significantly higher levels of SF IL-8 compared to OA (p=0.0020). No significant difference emerged across the three conditions in the serum levels of both chemerin and IL-8. IL-8 strongly correlated with inflammatory markers as ESR, CRP, IL-6 and TNF-α. Conclusions We observed similar chemerin SF and serum levels in the three conditions. Although flawed by some limitations, our findings support the emerging concept of OA as an inflammatory disorder. However the increased IL-8 levels we described in patients with inflammatory arthritis suggest a selective involvement of this pro-inflammatory and angiogenic cytokine in these conditions. Key words chemerin, interleukin-8, synovial fluid, rheumatoid arthritis, psoriatic arthritis, osteoarthritis Clinical and Experimental Rheumatology 2014; 32: 243-250. Chemerin and IL-8 in arthropathies / E. Valcamonica et al. Elisabetta Valcamonica, MD* Introduction served in RA patients (9). IL-8 has also Cecilia B. Chighizola, MD* Major achievements in understand- been identified as a pivotal player in an- Daniela Comi, MD ing the pathogenesis of arthropathies giogenesis, one of the key-mechanisms Orazio De Lucia, PhD have recently been made; however, for the maintenance and perpetuation of Laura Pisoni, MD Antonella Murgo, MD there is still much to unravel. It was re- chronic synovial inflammation (10, 11). Valentina Salvi, PhD cently demonstrated that the adipokine Assessing the concentration in the Silvano Sozzani, PhD chemerin mediates joint inflamma- synovial fluid (SF) of potential patho- Pier Luigi Meroni, MD tion and cartilage degradation. Initially genetic mediators may supply further *These authors made an equal thought to be restricted to metabolic insights into the etiopathogenesis of contribution to this study. activities, chemerin was later shown arthropathies. Therefore, the aim of Please address correspondence to: to be a potent chemotactic protein for this study was to investigate chemerin Pier Luigi Meroni, MD, Chemerin Receptor 23 (ChemR23)-ex- and IL-8 levels in the SF of patients Division of Rheumatology, pressing cells as macrophages, natural with immune-mediated inflammatory Istituto G. Pini, killer and plasmacytoid dendritic cells arthritides (RA and psoriatic arthritis, Pzza. C. Ferrari 1, 20122 Milan, Italy. (1). Chemerin is expressed mainly by PsA) and osteoarthritis (OA). To bet- E-mail: [email protected] adipocytes and epithelial cells and, to ter ascertain the local versus systemic Received on November 3, 2013; accepted a minor extent, by chondrocytes and fi- production of the study cytokines, we in revised form on November 12, 2013. broblast-like synoviocytes (FLS) (1, 2). also assessed serum chemerin and IL-8 © Copyright CLINICAL AND It is synthetised as an inactive precur- levels. In addition, chemerin and IL-8 EXPERIMENTAL RHEUMATOLOGY 2014. sor, then converted into the biologically were compared to IL-6 and TNF-α, active form by several proteases from two well-established mediators of joint inflammatory and coagulation cascades inflammation. (3). Chemerin expression is upregu- lated by lipopolysaccharide (LPS) and Materials and methods tumour necrosis factor (TNF)-α; serum Patients levels of chemerin were shown to be Twenty-six patients with a diagnosis associated with inflammatory mark- of immune-mediated inflammatory ar- ers such as TNF-α, interleukin (IL)-6 thritis and 11 with OA were recruited and C-reactive protein (CRP) (4). In in this study. All 37 patients were di- FLS from patients with rheumatoid ar- agnosed according to the criteria of the thritis (RA), the pro-inflammatory and American College of Rheumatology stimulatory effects of chemerin were (12-14). SF samples were obtained mediated by the activation of ERK1/2, when an arthrocentesis was performed p38MAPK and Akt (2). Moreover, in because of knee synovitis. Four patients human articular chondrocytes chemerin (2 with AR, 1 with PsA and 1 with OA) has been shown to increase the produc- underwent knee arthrocentesis two tion of TNF-α, IL-6, IL-1β, metallo- times six months apart. Clinical data proteinases (MMP)-1 and MMP-8. At including age, BMI, disease duration, higher concentrations, chemerin induc- VAS pain, DAS28 (in RA and PsA) and es MMP-2, MMP-3, MMP-13 and IL-8 radiographic grade (Kellegren’s classi- (5). IL-8 is a pro-inflammatory C-X-C fication system, (15)) were collected at chemokine previously characterised as the time of arthrocentesis. In addition, the principal agent of the recruitment serum samples were obtained from 13 and activation of neutrophils. In the patients (4 with AR, 6 with PsA and 3 synovium, IL-8 is constitutively secret- with OA) at the time of arthrocentesis. ed by synovial macrophages while FLS produce IL-8 only in the presence of Protein assays agonists such as IL-1α, IL-1β, TNF-α The SF and serum levels of chemerin, Funding: C.B. Chighizola is supported and LPS (6). More precisely, IL-8 ex- IL-8, IL-6 and TNF-α were determined by by a Research Grant co-financed by pression in FLS from RA patients is by commercially available enzyme- University of Milan and Dote Ricerca: induced upon activation of Toll-like re- linked immunosorbent assays (ELI- FSE, Regione Lombardia; V. Salvi is the recipient of a fellowship ceptor (TLR) 2 and TLR3, two innate SAs, R&D Systems, Minneapolis, from FIRC (Fondazione Italiana per la immunity receptors involved in inflam- MN, USA), following manufacturer’s Ricerca sul Cancro). mation (7, 8). In animal models, IL-8 instructions. The total protein contents This work was supported by injected intra-articularly was shown to of SF and serum samples (mg/ml) were IMI JU-funded project BeTheCure. induce joint inflammation with synovial measured using Bio-Rad Protein assay Competing interests: none declared. histological changes similar to those ob- (Bio-Rad Laboratories, Hercules, CA, 244 Chemerin and IL-8 in arthropathies / E. Valcamonica et al. USA), according to manufacturer’s in- upon diagnosis, gender and radiological (15 mg/week) and hydroxychloroquine structions. Experiments were all run in grade. Associations between SF and se- (400 mg/day) and 8/18 on leflunomide triplicates. The SF and serum concen- rum cytokine levels with demographic, (20 mg/day) and hydroxychloroquine trations of the four cytokines (ng/ml) clinical and biochemical variables were (400 mg/day); all were on corticoster- were then normalised to SF and serum determined by Spearman’s coefficient oid treatment (<5 mg/die). PsA patients total protein contents respectively and (r). SF and serum levels of the four study were all on salazopirine (3 gr/day), the expressed as ng/mg. Chemerin and IL-8 cytokines normalised to the total SF/se- OA subjects on non-steroidal inflam- were measured in 41 samples obtained rum protein contents were compared us- matory agents only. from 37 patients while TNF-α and IL-6 ing a matched-pair Mann-Whitney test. Of the 13 subjects whose serum and SF were assessed in 37 samples. Univariate, bivariate and multivariate samples were collected, 4 patients were logistic regression analyses were drawn diagnosed with RA, 6 with PsA and 3 Immunohistochemistry to investigate the relationship between with OA. 9 subjects (69%) were of fe- Synovial tissues for immunohisto- SF and serum levels of the four study male gender. Table II reports the demo- chemical analysis were obtained from 4 cytokines and diagnosis (defined as graphic and clinical characteristics, the RA patients who underwent knee syn- immune-mediated inflammatory arth- biochemical variables and the serum ovectomy. Tissues were formalin-fixed ritides versus OA). Statistical analysis and SF levels of chemerin, IL-8, IL-6 and paraffin embedded. Sections were was performed with
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