Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.

Koch, Alisa E.; Kunkel, Steven L.; Harlow, Lisa A.; Johnson, Bruce A.; Evanoff, Holly L.; Haines, G. Kenneth; Burdick, Marie D.; Pope, Richard M.; Strieter, Robert M.

doi:10.1172/jci115950

Cited by 590 publications

(421 citation statements)

References 42 publications

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“…In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5)(6)(7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9)(10)(11)(12).…”

mentioning

confidence: 63%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

109

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Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2؉ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1؉,CCR2؉ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2؉ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dosedependent proinflammatory effects of CCR2 mAb are taken into account.CCR2, a chemokine (CC motif) receptor, is considered a promising target for disorders such as multiple sclerosis, type II diabetes, and rheumatoid arthritis, and Phase I and II clinical trials are currently in progress (1). Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5-7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9-12).However, thus far, data from murine models of collagen-induced arthritis do not support CCR2 as a target for treatment of rheumatoid arthritis. We have previously shown that treatment with a blocking monoDrs. Brühl, Luckow,

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mentioning

confidence: 63%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

109

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“…In animal models of RA, this transformed appearance of RA synoviocytes could be mitigated by transferring the CDK inhibitor genes p16 INK4a and p21 Cip1 into inflamed joints (29,30). CDK-2, which is inhibited by p21 Cip1 and p27 Kip1 , is another key CDK: CDK-2/cyclin E complexes are required for the G 1 -to-S phase transition and initiation of DNA synthesis, whereas CDK-2/cyclin A complexes function during the progression of cells through S phase (31). Our in vitro finding that overexpression of miR124a caused G 1 phase arrest in RA FLS is indicative of a direct suppression of CDK-2 mRNA by miR-124a.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis

Nakamachi¹,

Kawano²,

Takenokuchi³

et al. 2009

Arthritis & Rheumatism

302

209

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Objective. To elucidate the role of microRNA (miRNA) in the pathogenesis of rheumatoid arthritis (RA), we analyzed synoviocytes from RA patients for their miRNA expression.Methods. Synoviocytes derived from surgical specimens obtained from RA patients were compared with those obtained from osteoarthritis (OA) patients for their expression of a panel of 156 miRNA with quantitative stem-loop reverse transcription-polymerase chain reaction. The miRNA whose expression decreased or increased in RA synoviocytes as compared with OA synoviocytes were identified, and their target genes were predicted by computer analysis. We used an in vitro system of enhancing the expression of specific miRNA by transfection of precursors into synoviocytes, and then we performed proliferation, cell cycle, and apoptosis assays, as well as enzyme-linked immunosorbent assays for cytokine production. The effects of transfection on predicted target protein and messenger RNA (mRNA) were then examined by Western blot analysis and luciferase reporter assay.Results. We found that miR-124a levels significantly decreased in RA synoviocytes as compared with OA synoviocytes. Transfection of precursor miR-124a into RA synoviocytes significantly suppressed their proliferation and arrested the cell cycle at the G 1 phase. We identified a putative consensus site for miR-124a binding in the 3 -untranslated region of cyclin-dependent kinase 2 (CDK-2) and monocyte chemoattractant protein 1 (MCP-1) mRNA. Induction of miR-124a in RA synoviocytes significantly suppressed the production of the CDK-2 and MCP-1 proteins. Luciferase reporter assay demonstrated that miR-124a specifically suppressed the reporter activity driven by the 3 -untranslated regions of CDK-2 and MCP-1 mRNA.Conclusion. The results of this study suggest that miR-124a is a key miRNA in the posttranscriptional regulatory mechanisms of RA synoviocytes.MicroRNA (miRNA) are a well-established class of small (ϳ22 nucleotides) endogenous noncoding RNAs that influence the stability and translation of messenger RNA (mRNA) (1). Using various computational and experimental approaches, hundreds of miRNA have been identified in numerous animal species. The miRNA genes are transcribed by RNA polymerase II as primary miRNA (pri-miRNA) (2,3). The RNase III enzyme Drosha then processes the nuclear pri-miRNA, yielding a ϳ70-nucleotide molecule known as precursor miRNA (pre-miRNA) (4), which is exported from the nucleus. Maturation of the pre-miRNA into miRNA is then mediated by the cytoplasmic enzyme Dicer (5), after which the mature miRNA is loaded into the RNA-induced silencing complex (RISC)

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“…Although MCP-I is originally reported to be an attractant for monocytes but not for neutrophils or lymphocytes [6], the cytokine has recently been shown to chemoattract T-lymphocytes in addition to monocytes [7,8]. Based on its in vitro and in vivo functions, the correlation of MCP-I expression and the pathologies or pathophysiologies have already been studied in several diseases and are still under investigation in a wide variety of immune and inflammatory diseases [1][2][3][4][5][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Expression of monocyte chemoattractant protein‐1 mRNA and protein in cultured human thyrocytes

et al. 1996

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Monocytes as well as lymphocytes infiltrate in the stroma of thyroid tissue in autoimmune and destructive thyroiditis. Monocyte chemoattractant protein-1 (MCP-I) is a cytokine that attracts T-lymphocytes as well as monocytes. Using human thyrocytes in primary cultures, we show that expression of MCP-1 mRNA and protein is remarkably stimulated by both interleukin-1 (IL-1) and tumor necrosis factor-~ (TNF-ct), and also that interferon-T (IFN-~/) by itself is a weak stimulant but has a synergistic activity with either IL-1 or TNF-c¢, The finding indicates that MCP-1 can be produced by thyrocytes themselves, suggesting a possible role of thyrocytes on accumulation of monocytes and T-lymphocytes to the tissue from the blood in autoimmune and destructive thyroiditis.

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Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.

Cited by 590 publications

References 42 publications

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis

Expression of monocyte chemoattractant protein‐1 mRNA and protein in cultured human thyrocytes

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