The main pro- and antiinflammatory cytokines in rheumatoid arthritis: interrelationships and pathogenetic significance

   Imbalance in the production of pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of rheumatoid arthritis (RA).

  The aim of the study. To determine the concentration and frequency of increase in serum of pro- and anti-inflammatory cytokines in patients with RA in the advanced stage of the disease, assessment of the relationship between them, clinical and laboratory activity of the disease and autoantibodies.

   Materials and methods. We examined 154 RA patients (41 men and 113) women, of average age (56.0 [50.0; 64.0] years), disease duration (9.4 [3.0; 13.0] years), seropositive 129 (83.8 %) for IgM rheumatoid factor (RF) and/or 106 (68.8 %) antibodies to cyclic citrullinated peptides (ACCP) with moderate to high (DAS 28-ESR – 5.40 [4.65; 6.00]) disease activity. The concentration of interleukin (IL), tumor necrosis factor α (TNF-α), interferon-γ (INF-γ), soluble CD 40 ligand (sCD 40L) in serum was determined by multiplex technology.

   Results. In RA patients, the concentration of IL-6, IL-23, IL-31, IL-33 and INF-γ was significantly higher, and TNF-α values were significantly lower than in controls. The levels of IL-1β, IL-17A, IL-17F, IL-25 and sCD 40L were not different from donors. IL-10 values were significantly higher than donors, and IL-4 values were not different from controls. In RA, the frequency of IL-33 elevation was 87.0 %, IL-6 51.6 %, IL-31 48.1 %, IL-17F 46.1 %, IL-23 42.9 % and INF-γ 39.0 %, IL-17A 29.9 %, IL-1β 26.6 %, TNF-α 23.4 %, IL-25 11.7 % and sCD 40L 3.2 % of patients. IL-33 hyperproduction was significantly predominant over other cytokines (p < 0.001). Elevated values of IL-10 were found in 16.2 % and IL-4 in 12.3 % of patients. Hyperproduction of proinflammatory cytokines, except IL-25 and sCD 40L, significantly prevailed over IL-4 and IL-10. Correlations of proinflammatory cytokines among themselves and with IL-4 and IL-10 were found. High values of IL-33 were associated only with IL-31. IL-4 and IL-10 concentrations were significantly correlated with each other. IL-6 concentration was found to be associated with DAS 28-ESR, CDAI and SDAI; IL-25 and sCD 40L were associated with CDAI and SDAI; IL-17A and IL-33 were associated with SDAI; IL-4 and IL-10, with CDAI and SDAI; IL-31 and IL-33, with CRP; TNF-α and INF-γ, with CRP; IL-17A, and IgM RF and ACCP; IL-31 and INF-γ, with IgM RF. IL-4 and IL10 were positively correlated with IgM RF, and IL-4 was negatively correlated with ADCP.

   Conclusions. In RA patients in the advanced stage of the disease, there is an imbalance between pro- and anti-inflammatory cytokines, with a predominance of IL-33 production. Despite the presence of interrelationships between cytokines, there are significant differences between them in associations with clinical indices, laboratory indicators of disease activity and autoantibodies.

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