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: 13.77). 12/2008; 118(11):3537-45. DOI: 10.1172/JCI36389
Source: PubMed

ABSTRACT 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.
    International Immunopharmacology 02/2015; 25(2). DOI:10.1016/j.intimp.2015.02.021 · 2.71 Impact Factor
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    • "Although TNF receptor engagement can also promote apoptosis under certain conditions, few cell types die in direct response to TNF treatment unless sensitized through co-exposure to transcriptional/translational inhibitors. A key aspect of TNF function is its ability to trigger the production of numerous pro-inflammatory cytokines and chemokines (Brennan and McInnes, 2008; Esche et al., 2005). TNF-induced cytokines and chemokines, such as IL-6, IL-8, GMCSF, CXCL1 and RANTES, can instigate and amplify immune responses through triggering the production of acute phase proteins, recruitment of neutrophils, macrophages and basophils to the site of inflammation and by triggering increased production of monocytes/macrophages from bone marrow. "
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    ABSTRACT: Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is well established that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.
    Biological Chemistry 08/2014; 395(10). DOI:10.1515/hsz-2014-0164 · 2.69 Impact Factor
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    • ". The cytokine IL-17 secreted from the T H 17 cells then activates macrophage and IL-21, and IL-23 released from macrophage also activates itself. Potency of IL-17 is accelerated via synergy with the effects of tumor necrosis factor [32] [33] [34]. In addition, extension of macrophage infiltration into the synovium enhances the severity and progression of RA by secreting IL-1, IL-6, TNF, and matrix metalloproteinase (MMPs) [32]. "
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    ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease particularly affecting elderly people which leads to massive bone destruction with consequent inflammation, pain, and debility. Allopathic medicine can provide only symptomatic relief. However, Zingiber officinale is a plant belonging to the Zingiberaceae family, which has traditionally been used for treatment of RA in alternative medicines of many countries. Many of the phytochemical constituents of the rhizomes of this plant have therapeutic benefits including amelioration of RA. This review attempts to list those phytochemical constituents with their reported mechanisms of action. It is concluded that these phytochemicals can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction. As the development of RA is a complex process, further research should be continued towards elucidating the molecular details leading to RA and drugs that can stop or reverse these processes by phytoconstituents of ginger.
    05/2014; 2014:159089. DOI:10.1155/2014/159089
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