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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    • "Of the two COX isoforms, COX-2 is not at all or only slightly expressed under basal conditions in many tissues, but it is upregulated in response to proinflammatory factors. Pathogenic crystals are able to induce a rapid enhancement of COX-2 gene expression in tissues and in human monocytes through tyrosine phosphorylation, leading to the transcription of PGE2, which, in addition to their pain-triggering role, may participate in other symptoms of gouty arthritic flares, such as early vasodilation, edema, and leukocyte migration [32]. Fewer findings are available concerning the effect of crystals on microsomal PGE synthase-1, which is generally upregulated coordinately with COX-2, in response to pro-inflammatory stimuli [33]. "
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    ABSTRACT: Crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction triggered by the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals in articular and periarticular tissues. Severe, acute pain constitutes the most important clinical symptom in patients affected by these diseases. Pain along with redness, warmness, swelling, and stiffness in the affected joint arises abruptly in gout and disappears when the acute phase of the attack resolves. While an acute joint attack caused by calcium pyrophosphate crystals can mimic a gout flare, basic calcium phosphate crystal arthritis gives rise to a series of clinical manifestations, the most severe of which are calcific periarthritis, mostly asymptomatic, and a highly destructive arthritis known as Milwaukee shoulder syndrome, which is characterized by painful articular attacks. Pain development in CIA is mediated by several inflammatory substances that are formed after cell injury by crystals. The most important of these molecules, which exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord, are prostaglandins, bradykinin, cytokines (in particular, interleukin (IL)-1β), and substance P. The pharmacological treatment of pain in CIA is strictly associated with the treatment of acute phases and flares of the disease, during which crystals trigger the inflammatory response. According to international guidelines, colchicines, nonsteroidal anti-inflammatory drugs, and/or corticosteroids are first-line agents for the systemic treatment of acute CIA, while biologics, namely anti-IL-1β agents, should be used only in particularly refractory cases. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · Bailli&egrave re s Best Practice and Research in Clinical Rheumatology
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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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