Iwamoto T, Okamoto H, Toyama Y et al.Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. FEBS J 275:4448-55

Institute of Rheumatology, Tokyo Women's Medical University, Japan.
FEBS Journal (Impact Factor: 4). 08/2008; 275(18):4448-55. DOI: 10.1111/j.1742-4658.2008.06580.x
Source: PubMed


Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regulated multi-step process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein-4 (MCP-4)/CCL13, pulmonary and activation-regulated chemokine (PARC)/CCL18, monokine induced by interferon-gamma (Mig)/CXCL9, stromal cell-derived factor 1 (SDF-1)/CXCL12, monocyte chemotactic protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3, and Fractalkine/CXC3CL1. Therefore, chemokines and chemokine-receptors are considered to be important molecules in RA pathology.

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Available from: Hiroshi Okamoto, Oct 06, 2014
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    • "Our group has recently shown that GPSM3 deficienct mice have reduced CAIA that is associated with a decreased transcript expression of the proinflammatory, monocyte-derived cytokines IL-6 and IL-1β, as well as of monocytespecific chemokine receptors in the joints [21]. TNF-α, IL-1β, and IL-6 are all produced by monocytes/macrophages , which are recruited to the inflamed synovium by chemokines such as CCL2/MCP-1 and CX3CL1/fractalkine, among numerous others [6] [7] [54] [55]. GPSM3 deficiency is seen to reduce monocyte chemotaxis toward CCL2, CX3CL1 and chemerin, and to enhance etoposide-induced apoptosis ex vivo [21], suggesting that GPSM3 affects monocytes through the regulation of chemokinereceptor signaling and its downstream intracellular sequelae. "
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    ABSTRACT: G protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of a family of proteins containing one or more copies of a small regulatory motif known as the GoLoco (or GPR) motif. GPSM3 interacts directly with Gα and Gβ subunits of heterotrimeric G proteins to regulate downstream intracellular signals initiated by G protein coupled receptors (GPCRs) that are activated via binding to their cognate ligands. GPSM3 has a selective tissue distribution and is highly expressed in immune system cells; genome-wide association studies (GWAS) have recently revealed that single nucleotide polymorphisms (SNPs) in GPSM3 are associated with chronic inflammatory diseases. This review highlights the current knowledge of GPSM3 function in normal and pathologic immune-mediated conditions.
    08/2014; 3(2):97-106.
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    • "Rheumatoid arthritis (RA) is a chronic joint disease characterized by massive infiltration of inflammatory cells into multiple joints, leading to hyperplasia of synovium and destruction of cartilage and bone [22]. Previous studies have defined the role of CX3CL1 in pathogenesis of RA and other chronic diseases such as polymyositis and dermatomyositis [23–26]. "
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    ABSTRACT: Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14 + monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas.
    Mediators of Inflammation 03/2014; 2014(41):480941. DOI:10.1155/2014/480941 · 3.24 Impact Factor
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    • "The role of chemokines in the pathogenesis of diseases, such as RA, is perhaps less well understood than that of cytokines, such as IL-1β and TNF-α (which are successfully targeted by biologic therapy in inflammatory disease [1]). However, numerous chemokines, including CCL3, CCL4, CXCL2 and IL-8, are elevated in both RA synovial tissue and synovial fluid, as well as in neutrophils isolated from RA joints [47], [48], [49], [50]. The success of anti-TNF therapy in treating patients with very active RA may therefore by explained, in part, by blockade of TNF-α-induced production of other mediators of inflammation, such as chemokines, by neutrophils and other immune cells. "
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    ABSTRACT: Neutrophils are central to the pathology of inflammatory diseases, where they can damage host tissue through release of reactive oxygen metabolites and proteases, and drive inflammation via secretion of cytokines and chemokines. Many cytokines, such as those generated during inflammation, can induce a similar "primed" phenotype in neutrophils, but it is unknown if different cytokines utilise common or cytokine-specific pathways to induce these functional changes. Here, we describe the transcriptomic changes induced in control human neutrophils during priming in vitro with pro-inflammatory cytokines (TNF-α and GM-CSF) using RNA-seq. Priming led to the rapid expression of a common set of transcripts for cytokines, chemokines and cell surface receptors (CXCL1, CXCL2, IL1A, IL1B, IL1RA, ICAM1). However, 580 genes were differentially regulated by TNF-α and GM-CSF treatment, and of these 58 were directly implicated in the control of apoptosis. While these two cytokines both delayed apoptosis, they induced changes in expression of different pro- and anti-apoptotic genes. Bioinformatics analysis predicted that these genes were regulated via differential activation of transcription factors by TNF-α and GM-CSF and these predictions were confirmed using functional assays: inhibition of NF-κB signalling abrogated the protective effect of TNF-α (but not that of GM-CSF) on neutrophil apoptosis, whereas inhibition of JAK/STAT signalling abrogated the anti-apoptotic effect of GM-CSF, but not that of TNF-α (p<0.05). These data provide the first characterisation of the human neutrophil transcriptome following GM-CSF and TNF-α priming, and demonstrate the utility of this approach to define functional changes in neutrophils following cytokine exposure. This may provide an important, new approach to define the molecular properties of neutrophils after in vivo activation during inflammation.
    PLoS ONE 03/2013; 8(3):e58598. DOI:10.1371/journal.pone.0058598 · 3.23 Impact Factor
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