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Differential expression of pro-inflammatory cytokines IL-15Ralpha, IL-15, IL-6 and TNFalpha in synovial fluid from rheumatoid arthritis patients.

Santos Savio A, Machado Diaz AC, Chico Capote A, Miranda Navarro J, Rodríguez Alvarez Y, Bringas Pérez R, Estévez del Toro M, Guillen Nieto GE - BMC Musculoskelet Disord (2015)

Bottom Line: 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.In addition we found correlation between the value of IL-15Ralpha in SF and disease activity score, DAS28.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. alicia.santos@cigb.edu.cu.

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.

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Correlation between cytokines concentration in SF from RA patients. Correlations among concentrations of IL-15Ralpha, IL-15, IL-6 and TNF alpha in SF from RA patients were analyzed using spearman’s rank correlation for all possible combinations. Correlations were significant between IL-6/ IL-15Ralpha (A) and IL-15/Il-15Ralpha (B), but not for IL-15Ralpha/TNFalpha (C), IL-6/TNFalpha (D), TNFalpha/IL-15 (E) or IL-6/IL-15 (F). r (the Spearman correlation coefficient), p (p value, was set at significant at 0.05).
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Fig3: Correlation between cytokines concentration in SF from RA patients. Correlations among concentrations of IL-15Ralpha, IL-15, IL-6 and TNF alpha in SF from RA patients were analyzed using spearman’s rank correlation for all possible combinations. Correlations were significant between IL-6/ IL-15Ralpha (A) and IL-15/Il-15Ralpha (B), but not for IL-15Ralpha/TNFalpha (C), IL-6/TNFalpha (D), TNFalpha/IL-15 (E) or IL-6/IL-15 (F). r (the Spearman correlation coefficient), p (p value, was set at significant at 0.05).

Mentions: Additionally, we performed correlation analysis among all studied cytokines. In correspondence with our previous report, we found a correlation between IL-15Ralpha and IL-6 (r = 0.4335, p = 0.008, Figure 3A). In current work we also found a correlation between IL-15Ralpha and IL-15 (r = 0.313, p = 0.01, Figure 3B). However, there was no positive correlation between IL-15Ralpha and TNFalpha (r = 0.08, p = 0.32) IL-15 and TNFalpha (r = −0.136, p = 0.23), IL-15 and IL-6 (r = 0.10, p = 0.29) or TNFalpha-IL-6 (r = 0.27, p = 0.07) (Figure 3C-F). Also we did the correlation analysis among values of IL-15Ralpha, DAS28, ERS and CRP for each patient at the moment for taking the sample. As a result we found a correlation between IL-15Ralpha and DAS28, but neither to ESR nor CRP. (Figure 4).Figure 3


Differential expression of pro-inflammatory cytokines IL-15Ralpha, IL-15, IL-6 and TNFalpha in synovial fluid from rheumatoid arthritis patients.

Santos Savio A, Machado Diaz AC, Chico Capote A, Miranda Navarro J, Rodríguez Alvarez Y, Bringas Pérez R, Estévez del Toro M, Guillen Nieto GE - BMC Musculoskelet Disord (2015)

Correlation between cytokines concentration in SF from RA patients. Correlations among concentrations of IL-15Ralpha, IL-15, IL-6 and TNF alpha in SF from RA patients were analyzed using spearman’s rank correlation for all possible combinations. Correlations were significant between IL-6/ IL-15Ralpha (A) and IL-15/Il-15Ralpha (B), but not for IL-15Ralpha/TNFalpha (C), IL-6/TNFalpha (D), TNFalpha/IL-15 (E) or IL-6/IL-15 (F). r (the Spearman correlation coefficient), p (p value, was set at significant at 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359511&req=5

Fig3: Correlation between cytokines concentration in SF from RA patients. Correlations among concentrations of IL-15Ralpha, IL-15, IL-6 and TNF alpha in SF from RA patients were analyzed using spearman’s rank correlation for all possible combinations. Correlations were significant between IL-6/ IL-15Ralpha (A) and IL-15/Il-15Ralpha (B), but not for IL-15Ralpha/TNFalpha (C), IL-6/TNFalpha (D), TNFalpha/IL-15 (E) or IL-6/IL-15 (F). r (the Spearman correlation coefficient), p (p value, was set at significant at 0.05).
Mentions: Additionally, we performed correlation analysis among all studied cytokines. In correspondence with our previous report, we found a correlation between IL-15Ralpha and IL-6 (r = 0.4335, p = 0.008, Figure 3A). In current work we also found a correlation between IL-15Ralpha and IL-15 (r = 0.313, p = 0.01, Figure 3B). However, there was no positive correlation between IL-15Ralpha and TNFalpha (r = 0.08, p = 0.32) IL-15 and TNFalpha (r = −0.136, p = 0.23), IL-15 and IL-6 (r = 0.10, p = 0.29) or TNFalpha-IL-6 (r = 0.27, p = 0.07) (Figure 3C-F). Also we did the correlation analysis among values of IL-15Ralpha, DAS28, ERS and CRP for each patient at the moment for taking the sample. As a result we found a correlation between IL-15Ralpha and DAS28, but neither to ESR nor CRP. (Figure 4).Figure 3

Bottom Line: 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.In addition we found correlation between the value of IL-15Ralpha in SF and disease activity score, DAS28.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Division, Center for Genetic Engineering and Biotechnology, Havana, CP 10600, Cuba. alicia.santos@cigb.edu.cu.

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.

Show MeSH
Related in: MedlinePlus