Deng, G. M., Zheng, L., Chan, F. K. & Lenardo, M. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nature Med. 11, 1066-1072

Laboratory of Immunology, Building 10, Room 11N311, 10 Center Drive, MSC 1892, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Medicine (Impact Factor: 27.36). 11/2005; 11(10):1066-72. DOI: 10.1038/nm1304
Source: PubMed


Tumor necrosis factor (TNF)-alpha has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-alpha are mediated by binding to TNF receptors TNFR1 (also known as P60) or TNFR2 (also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily.

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Available from: Francis Chan, Mar 25, 2014
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    • "Inhibition of TNF-a production TNF-a is a potent mediator of inflammation produced mainly by monocytes and macrophages, in response to pathogens and inflammatory processes. Like NO, it has an important role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and septic shock [6]. It has been shown that glycosylated flavonoids are able to inhibit TNF-a production by THP-1 cells stimulated with LPS [25]. "
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    • "Paraffin-embedded knee joint tissue sections (5 μm thick) were stained with hematoxylin and eosin. Histopathologic scoring of joint damage was performed under blinded conditions according to a scoring system widely used for evaluating synovitis, cartilage degradation and bone erosion [33]. "
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    ABSTRACT: Our objective was to determine the signaling pathway of interleukin-10 (IL-10) for modulating interleukin-17 (IL-17) expression in macrophages and the importance of this mediation in collagen-induced arthritis (CIA). Interleukin-10 knockout (IL-10-/-) mice and wild type (WT) mice were immunized with Chicken type II collagen (CII) to induce arthritis. The expressions of IL-17 and retinoid related orphan receptor gammat (RORgammat) in macrophages and joint tissues of the IL-10-/- mice and WT mice were analyzed by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription-polymerase chain reaction (QT-PCR), and Western blotting. The F4/80 macrophages and positive IL-17-producing macrophages in synovial tissues of the mice were determined by immunohistochemistry. The populations of classically activated macrophages (M1) and alternatively activated macrophages (M2) phenotypes were analyzed by flow cytometry. The expressions of genes associated with M1 and M2 makers were analyzed by QT-PCR. Compared to WT mice, IL-10-/- mice exacerbated CIA development, which associated with increased production of T helper cell 17 (TH17)/T helper cell 1 (TH1) pro-inflammatory cytokines and CII-specific immunoglobulin G2a (IgG2a) antibody after CII immunization. Macrophages in IL-10-/- mice had increased amounts of IL-17 and RORgammat than those in WT mice with CIA. Immunofluorescence microscopy showed that the number of IL-17-producing macrophages in synovial tissues were significantly higher in IL-10-/- mice than in WT mice. IL-10 deficiency might promote macrophage polarization towards the pro-inflammatory M1 phenotype that contributes to rheumatoid arthritis (RA) inflammation response. IL-10 inhibits IL-17 and RORgammat expression in macrophages and suppresses macrophages towards the pro-inflammatory M1 phenotype, which is important for IL-10 to mediate the pathogenesis of CIA.
    Full-text · Article · Apr 2014 · Arthritis research & therapy
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    • "Fourteen days after immunization with BiP or citBiP, DBA/1J mice were immunized with 50 μg bovine type II collagen intradermally at the tail base on day 14 with CFA and on day 35 with IFA. The arthritis score was determined by the degree of erythema, swelling, or ankylosis observed on each paw, as described elsewhere [29]. The mice were sacrificed at 50 days after the first CIA immunization. "
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