Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes.
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.
Guerne
P A
PA
Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, CA 92037.
Terkeltaub
R
R
Zuraw
B
B
Lotz
M
M
D002131:Calcium Pyrophosphate / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000378:metabolism; D003460:Crystallization; D017886:Durapatite; D006073:Gout / Q000378:metabolism; D006801:Humans; D006882:Hydroxyapatites / Q000494:pharmacology; D007163:Immunosorbent Techniques; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D009000:Monocytes / Q000378:metabolism*; D009500:Neutralization Tests; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*
D006882:Hydroxyapatites; D007375:Interleukin-1; D015850:Interleukin-6; D014527:Uric Acid; D017886:Durapatite; D002131:Calcium Pyrophosphate