Abstract

Crystals of monosodium urate (MSU) provide a dose-dependent stimulus for the production by human blood monocytes of tumor necrosis factor (TNF), a cytokine with proinflammatory properties; TNF activity was inhibited selectively by monoclonal antibody to TNF alpha. Biologically active cell-associated TNF activity peaked at 3 h and was exceeded at 6 h by extracellular activity, which peaked at 12-18 h. Comparable kinetics were observed with immunoreactive TNF alpha. TNF alpha mRNA accumulation in monocytes stimulated with MSU crystals appeared as a single peak at 2-4 h, kinetics compatible with rapid production of a short half-life transcript. In contrast, crystals of calcium pyrophosphate or of hydroxyapatite did not stimulate significant production of TNF or of message. Fresh tophaceous material from a patient with gout contained significant levels of TNF alpha and cells cultured from the tophus produced TNF alpha in vitro. In rheumatoid synovial cells, spontaneous release of TNF alpha was increased by in vitro exposure to MSU crystals. Taken together with earlier work, these results support an expanded view of gouty inflammation in which the crystal-stimulated production of cytokines provides a crucial link between crystal deposition and many of the clinical and pathological facts of both acute and chronic gouty arthritis.