Brennan FM, McInnes IBEvidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118: 3537-3545

Kennedy Institute of Rheumatology, Imperial College London, London, UK.
Journal of Clinical Investigation (Impact Factor: 13.22). 12/2008; 118(11):3537-45. DOI: 10.1172/JCI36389
Source: PubMed


A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.

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    • "Arthritis is characterized by the breakdown of joint tissue, due to various factors such as aging, stress, and diabetes. This process can be experimentally mimicked by stimulating a chondrocyte with TNF-α, IL-1, or LPS, which play prominent roles in the catabolism of articular cartilage [1] [3] [4]. TNF-α is known to induce inflammatory conditions and to clearly increase the production of degradable enzymes such as MMP, particularly collagenase 1 and 3. Therefore, to investigate the preventive effects of bee venom and its major peptides on cartilage degradation, TNF-α was used to stimulate chondrocytes. "
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    ABSTRACT: Bee venom is a natural ingredient produced by the honey bee (Apis mellifera), and has been widely used in China, Korea and Japan as a traditional medicine for various diseases such as arthritis, rheumatism, and skin diseases However, the regulation of the underlying molecular mechanisms of the anti-arthritis by bee venom and its major peptides is largely unknown. In this study, we investigated the potential molecular mechanisms underlying the anti-arthritis effect of bee venom and its major peptides, melittin and apamin, in tumor necrosis factor-α (TNF-α) responsive C57BL/6 mice chondrocyte cells. The bee venom and melittin significantly and selectively suppressed the TNF-α-mediated decrease of type II collagen expression, whereas the apamin had no effects on the type II collagen expression. We, furthermore, found that the bee venom and melittin inhibited the protein expression of matrix metalloproteinase (MMP)-1 and MMP-8, which suggests that the chondroprotective effect of bee venom may be caused by melittin. The inhibitory effects of melittin on the TNF-α-induced MMP-1 and MMP-8 protein expression were regulated by the inhibition of NF-kB and AP-1. In addition, melittin suppressed the TNF-α-induced phosphorylation of Akt, JNK and ERK1/2, but did not affect the phosphorylation of p38 kinase. These results suggest that melittin suppresses TNF-α-stimulated decrease of type II collagen expression by the inhibiting MMP-1 and MMP-8 through regulation of the NF-kB and AP-1 pathway and provision of a novel role for melittin in anti-arthritis action. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · International Immunopharmacology
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    • "Rheumatoid arthritis (RA) is a chronic and systemic autoimmune syndrome, which is characterized by massive synovial proliferation and inflammation and leads to the destruction of joint cartilage and bone [1]. In addition, many kinds of cells infiltrate into the joint cavity during arthritis, including immune cells (such as macrophage, T cells and B cells) and erosive cells such as bone resorptive osteoclasts. "
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    ABSTRACT: The lipoxygenase isoform of 5-lipoxygenase (5-LOX) is reported to be overexpressed in human rheumatoid arthritis synovial tissue and involved in the progress of inflammatory arthritis. However, the detailed mechanism of how 5-lipoxygenase regulates the inflammatory response in arthritis synovial tissue is still unclear. The aim of this study was to investigate the involvement of lipoxygenase pathways in TNF-α-induced production of cytokines and chemokines. Human synovial fibroblasts from rheumatoid patients were used in this study. 5-LOX inhibitors and shRNA were used to examine the involvement of 5-LOX in TNF-α-induced cytokines and chemokines expression. The signaling pathways were examined by Western Blotting or immunofluorescence staining. The effect of 5-LOX inhibitor on TNF-α-induced chemokine expression and paw edema was also explored in vivo in C57BL/6 mice. Treatment with 5-LOX inhibitors significantly decreased TNF-α-induced pro-inflammatory mediators including interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) in human synovial fibroblasts. Knockdown of 5-LOX using shRNA exerted similar inhibitory effects. The abrogation of NF-κB activation was involved in the antagonizing effects of these inhibitors. Furthermore, 5-LOX inhibitor decreased TNF-α-induced up-regulation of serum MCP-1 level and paw edema in mouse model. Our results provide the evidence that the administration of 5-LOX inhibitors is able to ameliorate TNF-α-induced cytokine/chemokine release and paw edema, indicating that 5-LOX inhibitors may be developed for therapeutic treatment of inflammatory arthritis.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "This systematic autoimmune disorder results in the accumulation of inflammatory cells such as T cells, B cells, and macrophages in the inflamed joints, which can lead to persistent synovitis and tissue destruction, typically articular cartilage destruction. Being a disabling and painful condition, RA often causes loss of mobility and function, and is commonly accompanied by substantial comorbid conditions in the cardiovascular, neurologic, and metabolic systems (1). The autoantigens are still unidentified in spite that RA is considered as autoimmune disease. "
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    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
    Full-text · Article · Aug 2014 · Frontiers in Oncology
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