Elevated Serum Interleukin 33 Is Associated with Autoantibody Production in Patients with Rheumatoid Arthritis

Abstract

Interleukin 33 (IL-33) is a novel cytokine involved in joint inflammation in animal models. We analyzed the expression of IL-33 in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and investigated its possible pathophysiological importance. The concentration of IL-33 was measured by ELISA in the serum of 223 patients with RA and 159 controls. Anticyclic citrullinated peptide, rheumatoid factor (RF)-IgA, and RF-IgG were tested by ELISA. Antikeratin antibody and antiperinuclear factor were tested by indirect immunofluorescence assay. Erythrocyte sedimentation rate, C-reactive protein, and immunoglobulins were measured by standard laboratory techniques. The association of IL-33 level with clinical and serologic features of RA was analyzed. We tested the change of IL-33 level following tumor necrosis factor (TNF-α) blockade therapy in 40 patients with RA. In contrast to almost no detectable IL-33 in osteoarthritis and healthy serum, IL-33 could be detected in 94 out of the 223 RA cases (42.2%). Serum IL-33 concentration was significantly higher in patients with RA than in control groups. The level of serum IL-33 decreased after anti-TNF treatment. The level of serum IL-33 was correlated with the production of IgM and RA-related autoantibodies including RF and anticitrullinated protein antibodies. However, no correlation was found between IL-33 concentration and acute-phase inflammation reactant or the score of the Disease Activity Index, suggesting a complex or indirect character of the link between IL-33 and the inflammation in RA. The level of IL-33 is abnormally elevated in RA serum. The elevation of serum IL-33 was at least partly attributed to excessive TNF-α in RA. IL-33 might be involved in the regulation of autoantibody production in RA.