title: Differential expression of pro-inflammatory cytokines IL-15Ralpha, IL-15, IL-6 and TNFalpha in synovial fluid from rheumatoid arthritis patients.
abstract: BACKGROUND
  Pro-inflammatory cytokines are directly implicated in the pathogenesis of Rheumatoid arthritis (RA). Variable clinical response to cytokine targeted therapies as TNFalpha and IL-6, strongly highlights the heterogeneity of inflammatory process in RA. Another cytokine, IL-15 has also been related to the inflammatory process in RA. Recently we described for the first time, the presence of its specific receptor, IL-15Ralpha, in synovial fluid (SF). The aim of this work was to compare the expression profile of IL-15Ralpha, its ligand IL-15, TNFalpha and IL-6 and how these cytokines are correlated in SF from RA patients taking as a reference Osteoarthritis (OA), an articular but not autoimmune disease.
  
  
  METHODS
  Synovial fluids were obtained from the knee joints of 60 patients, 30 with confirmed diagnosis of RA and 30 with OA diagnosis. The levels of TNFalpha, IL-6, IL-15 and IL-15Ralpha were measured by ELISA. A statistical analysis was performed with GraphPad Prism v5.0 using the Mann-Whitney U test and Spearman's rank correlation. A cluster analysis was run in MeV software v4.9.0 and differences across clusters were evaluated by an ANOVA including post-test analysis.
  
  
  RESULTS
  We found higher and significant levels of TNFalpha, IL-6 and IL-15Ralpha but not of IL-15 in RA compared with the OA group. Additionally, a high inter-individual variability in the levels of these 4 cytokines was observed in RA, although we identified 4 patients' subgroups by cluster analysis of cytokines concentration in SF. We also found a positive correlation between IL-15Ralpha-IL-6 and IL-15Ralpha-IL-15, but not for other pairs of cytokines in RA. In addition we found correlation between the value of IL-15Ralpha in SF and disease activity score, DAS28.
  
  
  CONCLUSIONS
  In our current work we found a high inter-individual variability in the levels of TNFalpha, IL-6, IL-15 and IL-15Ralpha in SF of RA patients and were identified four principal clusters of cytokines concentration in SF, suggesting the importance of identifying disease subset of patients for personalized treatment. Finally, we found a correlation between IL-15Ralpha-IL-6, IL-15Ralpha-IL-15, but we did not find any correlation between other pairs of studied cytokines in SF.
authors: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. alicia.santos@cigb.edu.cu.
authors: Alicia
authors: A
authors: Santos Savio
authors: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. ana.machado@cigb.edu.cu.
authors: Ana Cecilia
authors: AC
authors: Machado Diaz
authors: Rheumatology Department, H. Ameijeiras Hospital, San Lazaro 701, Havana, Cuba. aracelica@infomed.sld.cu.
authors: Araceli
authors: A
authors: Chico Capote
authors: Bioinformatics Department, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. jamilet.miranda@cigb.edu.cu.
authors: Jamilet
authors: J
authors: Miranda Navarro
authors: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. yunier.rodriguez@cigb.edu.cu.
authors: Yunier
authors: Y
authors: Rodríguez Alvarez
authors: Bioinformatics Department, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. ricardo.bringas@cigb.edu.cu.
authors: Ricardo
authors: R
authors: Bringas Pérez
authors: Rheumatology Department, H. Ameijeiras Hospital, San Lazaro 701, Havana, Cuba. mestevez@infomed.sld.cu.
authors: Miguel
authors: M
authors: Estévez del Toro
authors: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. gerardo.guillen@cigb.edu.cu.
authors: Gerardo E
authors: GE
authors: Guillen Nieto
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D016000:Cluster Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis*; D019409:Interleukin-15 / Q000032:analysis*; D015850:Interleukin-6 / Q000032:analysis*; D007719:Knee Joint / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000175:diagnosis / Q000276:immunology; D053647:Receptors, Interleukin-15 / Q000032:analysis*; D013582:Synovial Fluid / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D015415:Biomarkers; C569274:IL15 protein, human; C508024:IL15RA protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D019409:Interleukin-15; D015850:Interleukin-6; D053647:Receptors, Interleukin-15; D014409:Tumor Necrosis Factor-alpha