Gout: diagnosis, pathogenesis, and clinical manifestations

Agudelo, Carlos A.; Wise, Christopher M.

doi:10.1097/00002281-200105000-00015

Cited by 78 publications

(35 citation statements)

References 38 publications

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“…By different experimental approaches, the authors demonstrated that uric acid, most probably in its biologically active form, MSU crystals, acts as an adjuvant by stimulating dendritic cell maturation and significantly enhancing CD8 ϩ T cell responses. Because large amounts of uric acid can be produced from tissue injury in vivo (48) and MSU crystals precipitate in joints of hyperuricemic patients (11), uric acid seems to be one of the main endogenous danger signals that activate the immune response against injured cells and dying tissues (47). Further supporting a role for uric acid in immune surveillance, it was shown that MSU crystals and IL-1 synergistically induce osteoblastic PGE 2 expression (49), a factor implicated in bone resorption (50), probably contributing to chronic arthritis.…”

Section: Discussionmentioning

confidence: 99%

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Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

Jaramillo

Naccache

Olivier

2004

The Journal of Immunology

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Elevated NO production has been detected in patients suffering from various arthropathies; however, its role and regulation during gouty arthritis remain largely unexplored. Monosodium urate (MSU) crystals, the causative agent of gout, have been shown to induce NO generation in vivo and inducible NO synthase (iNOS) expression in human monocytes. The present study was designed to evaluate the ability of MSU crystals to modulate macrophage (Mφ) iNOS expression and NO synthesis and to investigate the molecular mechanisms underlying these cellular responses. We found that MSU crystals did not induce NO production in murine J774 Mφ. However, a synergistic effect on the level of iNOS expression and NO generation was observed in cells exposed to MSU crystals in combination with IFN-γ. Characterization of the second messengers involved revealed the requirement of IFN-γ-mediated Janus kinase 2/STAT1α activation even though MSU crystals did not modulate this signaling cascade by themselves. MSU crystals exerted their up-regulating effect by increasing extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and NF-κB nuclear translocation in response to IFN-γ. The use of specific inhibitors against either NF-κB or the ERK1/2 pathway significantly reduced MSU + IFN-γ-inducible NF-κB activity, iNOS expression, and NO production. Altogether, these data indicate that MSU crystals exert a potent synergistic effect on the IFN-γ-inducible Mφ NO generation via ERK1/2- and NF-κB-dependent pathways. Understanding the molecular mechanisms through which MSU crystals amplify Mφ responses to proinflammatory cytokines such as IFN-γ will contribute to better define their role in NO regulation during gout, in particular, and inflammation, in general.

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Section: Discussionmentioning

confidence: 99%

“…Gouty arthritis results from intra-articular deposition of monosodium urate (MSU) crystals in individuals with elevated serum concentrations of uric acid (11). MSU crystals activate a number of acute inflammatory pathways in various types of leukocytes that may induce and/or amplify an acute attack of gout (12).…”

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confidence: 99%

Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

Jaramillo

Naccache

Olivier

2004

The Journal of Immunology

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“…Acute attacks of gout are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint [1]. Gouty arthritis is caused by the disorder of nucleic acid metabolism that leads to monosodium urate (MSU) microcrystals deposition in the articular and periarticular tissue [2].…”

Section: Introductionmentioning

confidence: 99%

A Role of Piperine on Monosodium Urate Crystal-Induced Inflammation—An Experimental Model of Gouty Arthritis

2010

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In the present study, the anti-inflammatory effect of piperine was investigated on monosodium urate crystal-induced inflammation in mice, an experimental model for gouty arthritis, and compared it with that of the nonsteroidal anti-inflammatory drug, indomethacin. The levels of lysosomal enzymes, lipid peroxidation, tumor necrosis factor-α, and paw volume were increased significantly, and the activities of antioxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon piperine (30 mg/kg b.wt, i.p.) treatment. In vitro, piperine (50/100 ug/ml) suppressed the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration-dependent manner when compared to control cells. Thus, the present study clearly indicated that piperine inhibit the monosodium urate crystal-induced inflammation and can be regarded as therapeutic drug for the treatment of acute gouty arthritis.

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“…Gouty arthritis is characterized by joint inflammation as a result of intra-articular deposition of monosodium urate (MSU) 1 crystals in individuals with elevated serum concentrations of uric acid (1). MSU crystals initiate, amplify, and sustain intense attacks of acute inflammation because of their ability, among others, to stimulate the release of proinflammatory mediators, leading to endothelium activation and leukocyte recruitment (2).…”

mentioning

confidence: 99%

Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

Jaramillo

Godbout

Naccache

et al. 2004

Journal of Biological Chemistry

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Chemokine production has been associated with leukocyte infiltration into the joint during gouty arthritis, and monosodium urate (MSU) crystals, the causative agent of this arthropathy, have been shown to modulate their expression. In the present study, we investigated the transductional mechanisms underlying this cellular regulation in the murine macrophage cell line B10R. We report that MSU crystals rapidly and transiently increase mRNA levels of various chemokines in a concentration-dependent manner. Examination of second messenger activation revealed that macrophage exposure to MSU crystals led to MEK1/2, ERK1/2, and inhibitory protein B␣ phosphorylation as well as to NF-B and AP-1 nuclear translocation. Of interest, specific blockage of the ERK1/2 pathway drastically reduced up-modulation of MSU crystal-mediated chemokine production and activation of nuclear factors. Similarly, selective inhibition of NF-B suppressed NF-B DNA binding activity and the induction of all chemokine transcripts. These findings indicate that ERK1/2-dependent signals seem to be required for AP-1 and NF-B activation and subsequent mRNA expression of the various macrophage chemokines. In addition, transcription and stability assays performed in presence of actinomycin D showed that MSU crystal-mediated MIP-1␤ mRNA up-regulation resulted solely from transcriptional control, whereas that of MIP-1␣, MIP-2, and MCP-1 was due to both gene transcription activation and mRNA posttranscriptional stabilization. Overall, the results of this study help to define the molecular events that govern macrophage chemokine regulation in response to MSU crystals, which is of paramount importance to better understand, and eventually to tame, the inflammatory response during acute gout.

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Gout: diagnosis, pathogenesis, and clinical manifestations

Cited by 78 publications

References 38 publications

Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

A Role of Piperine on Monosodium Urate Crystal-Induced Inflammation—An Experimental Model of Gouty Arthritis

Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

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