Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

Nanki, Toshihiro; Nagasaka, Kenji; Hayashida, Kenji; Saita, Yuji; Miyasaka, Nobuyuki

doi:10.4049/jimmunol.167.9.5381

Cited by 179 publications

(152 citation statements)

References 29 publications

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“…Conversely, chemokines may also stimulate the release of proinflammatory cytokines. For instance, CCL3 can stimulate the synthesis of IL-1, IL-6, and TNF␣ (26), and CCL5 can induce the production of IL-6 and IL-8 (27).…”

Section: Discussionmentioning

confidence: 99%

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Lee¹,

Zhao²,

Kim³

et al. 2007

Arthritis & Rheumatism

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Objective. To examine genetic polymorphisms in the chemokine pathway, and to assess their interactions in relation to susceptibility to systemic sclerosis (SSc).Methods. To identify the risk of SSc conferred by genetic polymorphisms in the chemokine pathway, 10 single-nucleotide polymorphisms (SNPs) from 8 candidate genes were studied in 99 patients with SSc and 198 age-and sex-matched controls in a Korean population. SNPs were genotyped by polymerase chain reactionrestriction fragment length polymorphism or sequencespecific primer methods. Genetic associations between each SNP and SSc risk, calculated as odds ratios with 95% confidence intervals, were estimated using chisquare tests. Haplotypes for the 2 polymorphisms in the gene CCL5 (RANTES) were constructed, and their associations with SSc were tested. Gene-gene interactions were investigated using a recently described novel method, and the results were confirmed by conditional logistic regression. Adjustment for multiple testing was based on Bonferroni correction.Results. There was significant evidence of genegene interaction between polymorphisms in the genes CXCL8 (interleukin-8) and CCL5, and both of these were associated with an increased risk of SSc. This SNP-SNP interaction was confirmed by 2 independent statistical methods. The associations remained significant after Bonferroni adjustment for multiple testing. No significant association between each individual SNP or haplotype and the risk of SSc was found.Conclusion. Crosstalk between the 2 chemokines CXCL8 and CCL5 may contribute to the susceptibility to SSc.

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Section: Discussionmentioning

confidence: 99%

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Lee¹,

Zhao²,

Kim³

et al. 2007

Arthritis & Rheumatism

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“…There are several other reports that suggest the relevance of MAPK activation to the immunopathogenesis of RA (48)(49)(50)(51)(52). However, no report has described the effects of MAPK pathway inhibitors on the ex vivo cytokine production by freshly isolated synovial cells from RA patients.…”

Section: Discussionmentioning

confidence: 99%

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

Harigai¹,

Hara²,

Kawamoto³

et al. 2004

Arthritis & Rheumatism

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Objective. To determine the signal transduction pathways in CD14؉ synovial cells from patients with rheumatoid arthritis (RA) after CD40 ligation, and to examine their role in amplifying synovial inflammation in affected joints.Methods. Expression of messenger RNA was analyzed using quantitative reverse transcriptionpolymerase chain reaction. Cytokines and chemokines were measured using enzyme-linked immunosorbent assay. Activation of kinases was detected using Western blotting. Nuclear translocation of NF-B was examined using immunohistochemistry. CD14؉ synovial cells were enriched using magnetic cell sorting. Fibroblastlike synoviocytes (FLS) were obtained by passaging primary synovial cell culture.Results. Stimulation of CD14؉ synovial cells from RA patients by recombinant soluble CD154 (rsCD154) significantly induced expression of tumor necrosis factor ␣ (TNF␣),

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“…For example, skin, bone marrow, and RA synovial fluid fibroblasts all spontaneously make IL-6 [110][111][112]. Increased levels of TNF-α, IL-6, IFN-γ [113] and IL-17A [114] were found when synovial fibroblasts were cultivated with T cells.…”

Section: Fibroblast Products As Promoters Of Inflammationmentioning

confidence: 99%

“…For instance, CCL2 (monocyte chemotactic protein-1 or MCP-1), CCL5 (RANTES), and CXCL12 (SDF-1) have all been shown to enhance IL-6 and IL-8 production by RA synovial fibroblasts [111]. IL-8 is a chemoattractant for neutrophils and thus a regulator of acute, innate inflammation, but also a promoter of angiogenesis.…”

Section: Fibroblasts and Trafficking: Chemokines And Angiogenesismentioning

confidence: 99%

“…TGF-β1 induces CXCL12 production while TNF-α and IL-1β give rise to CCL5 production. All three of these cytokines lead to enhanced CCL2 expression [111]. The cytokine milieu thus alters which cell types will be summoned to an inflammatory site, including the tumor microenvironment, based on which chemokines are released.…”

Section: Fibroblasts and Trafficking: Chemokines And Angiogenesismentioning

confidence: 99%

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T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

Cited by 179 publications

References 29 publications

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

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