Inflammatory microcrystals stimulate interleukin‐6 production and secretion by human monocytes and synoviocytes

Abstract

Crystal‐related joint diseases are often associated with systemic inflammatory manifestations, including increased levels of acute‐phase proteins, leukocytosis, and fever. Recently, interleukin‐6 (IL‐6) has been identified as a pluripotent mediator of inflammatory and immunologic responses and the major hepatocyte‐stimulating factor. In this study, we demonstrated that monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, and to a lesser extent, hydroxyapatite crystals, increased IL‐6 production by synoviocytes and monocytes in vitro. Immunoprecipitation experiments showed that MSU and CPPD crystals, but not hydroxyapatite crystals, were able to increase the release of newly synthesized IL‐6. Crystal‐induced IL‐6 stimulated acute‐phase protein synthesis, immunoglobulin production, and hybridoma cell proliferation, which was neutralized by a specific antibody to IL‐6. High levels of IL‐6 were found in synovial fluid from patients with gout and pseudogout. These results demonstrate that MSU and CPPD crystals can induce IL‐6 production in synoviocytes and monocytes, and that synovial fluid from patients with gout and pseudogout contains high levels of IL‐6. Crystal‐induced IL‐6 is likely to be an important mediator of inflammatory responses in acute gout and pseudogout.