Interleukin-34 produced by human fibroblast-like synovial cells in rhematoid arthritis supports osteogenesis

Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Arthritis research & therapy (Impact Factor: 3.75). 01/2012; 14(1):R14. DOI: 10.1186/ar3693
Source: PubMed


Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.
IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNFα) for 24 hours and used for functional assay.
IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.
These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.

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    • "In RA patients, it was elevated in synovium, synovial fluid (SF), and FLS. The secretion of IL-34 was upregulated in FLS by TNF-α or IL-1β induction and was mediated by the transcription factor nuclear factor κB (NF-κB) and activation of c-Jun N-terminal kinase (JNK), indicating its osteoclastogenic role in RA [76, 77]. "
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    ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Although major therapeutic advances have been made in recent years, there is no cure for the disease. Current medications mainly reduce inflammation in order to relieve pain and slow joint damage, but many have potentially serious side effects. Therefore, to find specific biomarkers will benefit both RA patients to find relief from the disease and physicians to monitor the disease development. A number of biomarkers have been discovered and used clinically, and others are still under investigation. The autoantibodies, which are widely used in diagnosis and prognosis, novel biomarkers, which reflect clinical disease activity, and newly found biomarkers and pathogenic-related cytokines are discussed in this review.
    Research Journal of Immunology 08/2014; 2014:698192. DOI:10.1155/2014/698192
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    • "Pretreatment of 100 μM CAPE markedly inhibited TNF-α-induced IL-34 expression in MC3T3-E1 cells, indicating that NF-κB is involved in the expression of IL-34 in these cells. Previously, it was reported that TNF-α-induced IL-34 expression in synovial fibroblasts was mediated through the activation of NF-κB (22,23). NF-κB mediates the expression of numerous inflammatory genes, including IL-6 and ICAM-1, in rat and human osteoblast-like cells, such as UMR106 and MG63 cells (16,17,24,25). "
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    ABSTRACT: Osteoblasts produce various types of cytokines under pathological conditions and control osteoclast differentiation. Tumor necrosis factor-α (TNF-α) has been demonstrated to exert complex effects in osteoblasts under local inflammatory conditions, including in periodontal and periapical diseases. Interleukin-34 (IL-34) has been recently identified as a novel regulatory factor for the differentiation and function of osteoclasts. The present study provides the first evidence, to the best of our knowledge, that the expression of IL-34 is induced by TNF-α through nuclear factor-κB (NF-κB) activation in MC3T3-E1 osteoblastic cells. TNF-α induced IL-34 expression in a dose- and time-dependent manner. Immunocytochemistry with an NF-κB antibody demonstrated that NF-κB was mainly localized in the cytoplasm of the untreated MC3T3-E1 cells. Rapid translocation of NF-κB from the cytoplasm to the nucleus was observed in the cells treated with TNF-α for 15 min. Translocation and transcriptional activity of NF-κB were also determined by western blotting and a luciferase reporter assay, respectively. Pretreatment with 100 µM CAPE, an inhibitor of NF-κB, significantly inhibited TNF-α-induced IL-34 expression. These results indicate that TNF-α induces IL-34 expression via NF-κB in osteoblasts.
    Molecular Medicine Reports 06/2014; 10(3). DOI:10.3892/mmr.2014.2353 · 1.55 Impact Factor
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    • "In this paper we show that activation of these pathways are required for TNF-α and IL-1β to stimulate IL-34 which is in line with results in other cell types e.g. synovial fibroblasts [10], [11] and osteoblasts [30]. IL-34 could thus be a down-stream effector of the pro-inflammatory cytokines TNF-α and IL-1β and thereby induce osteoclast formation and bone resorption. "
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    ABSTRACT: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and Interleukin-1Β (IL-1β) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-α, IL-1β, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-α and IL-1β, regulated by the transcription factor nuclear factor kappa B (NF-κΒ) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-α and IL-1β, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis.
    PLoS ONE 12/2013; 8(12):e81665. DOI:10.1371/journal.pone.0081665 · 3.23 Impact Factor
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