Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes

Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia.
Blood (Impact Factor: 10.45). 04/1998; 91(5):1769-76.
Source: PubMed


The formation and deposition of monosodium urate (MSU) microcrystals in articular and periarticular tissues is the causative agent of acute or chronic inflammatory responses known as gouty arthritis. Mononuclear phagocyte activation is involved in early triggering events of gout attacks. Because stimulated mononuclear phagocytes can constitute an important source of the inducible isoform of cyclooxygenase (COX-2), we evaluated the effects that proinflammatory microcrystals might have on COX-2 protein expression in crystal-stimulated monocytes. We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Crystal-induced de novo synthesis of COX-2 was dependent on transcriptional and translational events. Inhibition of tyrosine phosphorylation, by herbimycin A, blocked crystal-induced COX-2. Similarly, an inhibitor of the p38 mitogen-activated protein kinase, SB 203580, inhibited the stimulation of COX-2. Colchicine inhibited crystal-induced COX-2. In all cases, prostanoid synthesis was concomitantly inhibited. Taken together, these results implicate COX-2 in the development of MSU-induced inflammation.

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    • "These effects are mediated by prostanoids, such as PGE2. In vitro studies have shown that MSU stimulates COX-2 protein expression in human monocytes and triggers the production of PGE2 [23]. Kant et al. demonstrated that hyperuricemia results in the upregulation of COX-2 immunoreactivity in kidney tissue [24]. "
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    • "Monosodium urate (MSU) crystals are among the most potent proinflammatory stimuli, and an innate immune inflammatory response to the crystal surface is intimately involved in the pathology of gouty arthritis [2]. Cell activation by MSU microcrystals is a central feature of acute gouty arthritis and proinflammatory microcrystals can interact with all of the major synovial cell types, including neutrophils, monocytes/macrophages, and fibroblast-like (type B) synoviocytes [3] [4]. In monocytes, for example, microcrystals stimulate the synthesis of a number of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, IL- 8, and tumor necrosis factor-alpha (TNF-α) [4]. "
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    • "The mode of action of this mixture seems to be owing to both a reduction of pro-inflammatory factors and a stimulation of at least one potentially anti-inflammatory factor, PGD2. TNF-α, IL-6 and PGE2 all have important roles in inflammatory arthropathies, including gout [26-28]. Moreover, the levels PGE2 and TNF-α are elevated in the inflamed rat air pouch [14], and, in preliminary studies of the microarray analysis of isolated murine air pouch membranes stimulated with MSU crystals, we have recently identified IL-6 as an MSU crystal-induced cytokine in the air pouch membrane and localized its expression to membrane fibroblasts and inflammatory cells [18]. "
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