Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8

Nishimura, Akito; Akahoshi, Tohru; Takahashi, Michio; Takagishi, Kenji; Itoman, Moritoshi; Kondo, Hirobumi; Takahashi, Yuichi; Yokoi, Kenji; Mukaida, Naofumi; Matsushima, Kouji

doi:10.1002/jlb.62.4.444

Cited by 98 publications

(73 citation statements)

References 18 publications

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“…37 Uric acid crystal stimulation also leads to the increased expression of TNF-a and IL1b in synovial fluid mononuclear cells. 38 TNF-a or IL-1b can potently induce the expression of CXCL8 in cultured FLS.…”

Section: Discussionmentioning

confidence: 99%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses. However, the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) have not been elucidated. Therefore, we investigated the in vitro effects of monosodium urate crystals, alone or in combination with the inflammatory cytokines tumor-necrosis factor (TNF)-a or interleukin (IL)-1b, on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals. Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6, the chemokine CXCL8 and the matrix metalloproteinase (MMP)-1 from both normal and RA-FLS (all P,0.05). Moreover, the additive or synergistic effect on the release of IL-6, CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-a or IL-1b. Further experiments showed that the release of the measured inflammatory cytokine, chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway. Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA. Keywords: cytokines; fibroblast-like synoviocytes; rheumatoid arthritis; signal transduction; uric acid INTRODUCTION Arthritis is the most common cause of joint pain and physical disability in developed countries and worldwide. 1 Gout is an acute inflammatory arthritis whose incidence has increased over the past decade, which is characterized by elevated serum urate concentrations and recurrent attacks by intra-articular uric acid crystal deposition. 2 Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with 1% prevalence in industrialized countries, which is characterized by cytokinemediated inflammation of the synovium and destruction of cartilage and bone. 3 Uric acid crystal-mediated gouty attacks have also been observed in patients with RA. 4,5 Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells in synovial joints that play crucial roles in both joint damage and the propagation of inflammation in arthritic diseases. 6 The ability of FLS to erode cartilage is a multistep process that includes the attachment of FLS onto cartilage and the synthesis of matrix metalloproteinases (MMPs) such as MMP-1. 7 Additionally, FLS secrete receptor activator of nuclear factor-kB ligand, which can attract macrophages from the vasculature, stimulate the differentiation of vascular-and tiss...

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Section: Discussionmentioning

confidence: 99%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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“…Notably, monocyte IL-8 production has been proposed as a major mechanism mediating MSU crystal-induced neutrophil migration (6,10,11). Further supporting a role for mononuclear phagocytes as a source of chemokines during gout, we provide evidence for the induction of multiple CC and CXC chemokine transcripts (MIP-1␣, MIP-1␤, MCP-1, and MIP-2) in macrophages following stimulation by MSU crystals.…”

Section: Discussionmentioning

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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“…Specifically, injection of rabbit IL-8 into rabbit knee joint cavities induced massive neutrophil accumulation, the release of neutrophil elastase resulting in cartilage destruction, and the induction of IL-1␤ and IL-1R antagonist expression (28). In acute arthritis induced by rabbit knee joint injection of LPS or monosodium urate crystals, IL-8 levels in synovial fluid and tissue were significantly elevated before the influx of leukocytes (primarily neutrophils) (29,30). A neutralizing IL-8-specific Ab was shown to inhibit LPS-, monosodium urate crystal-, or IL-1␣-induced leukocyte infiltration into rabbit knee joints, as well as to protect from joint swelling and tissue damage (30,31).…”

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confidence: 99%

“…In acute arthritis induced by rabbit knee joint injection of LPS or monosodium urate crystals, IL-8 levels in synovial fluid and tissue were significantly elevated before the influx of leukocytes (primarily neutrophils) (29,30). A neutralizing IL-8-specific Ab was shown to inhibit LPS-, monosodium urate crystal-, or IL-1␣-induced leukocyte infiltration into rabbit knee joints, as well as to protect from joint swelling and tissue damage (30,31). Similarly, in LPS-induced rabbit arthritis, elevated synovial fluid GRO levels preceded knee joint leukocyte influx, which was inhibited 54% by a neutralizing GRO-specific Ab, 48% by anti-IL-8 IgG, and 70% by a combination of the two Ab specificities (32).…”

mentioning

confidence: 99%

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

Podolin

Bolognese

Foley

et al. 2002

The Journal of Immunology

146

112

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Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits 125I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC50 = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC50 = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-α, IL-8, PGE2, leukotriene B4, and leukotriene C4 levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-α and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC50 = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.

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Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8

Cited by 98 publications

References 18 publications

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

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

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

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