Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β production.

Objective: Innate immune responses activate synoviocytes and recruit inflammatory cells into the rheumatoid joint. Type I interferons (IFNs) play a role in autoimmunity, and IFN gene transcription is activated by IFN-regulatory factors (IRFs) in response to innate sensor recognition. The purpose of this study was to examine the effect of genetic deficiency of IRF-7 in a passive K/BxN serum-transfer model of arthritis.

Targeting interferon regulatory factors to inhibit activation of the type I IFN response: implications for treatment of autoimmune disorders.

The type I interferon (IFN) response plays a critical role in autoimmunity and is induced by innate receptor ligation and activation of IFN-regulatory factors (IRF). The present study investigated the roles and functional hierarchy of IRF3, IRF5, and IRF7 in expression of cytokines, chemokines, and matrix metalloproteinases in human THP1 monocytic cells. Targeted IRF knockdown was followed by evaluation of gene expression, promoter activation, and mRNA stability to determine the role of IRF as potential targets for modulating IFN responses in patients with autoimmune diseases.

Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3.

Innate immune responses contribute to synovial inflammation in rheumatoid arthritis. The present study was designed to investigate the contribution of IFN regulatory factor (IRF)3 and IRF7 to type I IFN-regulated gene expression in synoviocytes. Fibroblast-like synoviocytes were stimulated with polyinosinic-polycytidylic acid (poly [I-C]) after transfection with IRF3 or IRF7 small interfering RNA to knockdown transcription factor expression.

Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases.

JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS).

Primer: signal transduction in rheumatic disease--a clinician's guide.

Signaling pathways enable cells to respond and adapt to environmental stimuli. For instance, extracellular ligands, such as proinflammatory cytokines or pathogen components, bind receptors on the surface of cells that trigger downstream signaling cascades driven by enzymes called kinases. Ultimately, kinases activate transcription factors that bind to DNA and alter the expression of target genes, the products of which allow the cell to respond to the initial stimulus.

Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3.

Objective: The rheumatoid synovium displays characteristics of Toll-like receptor (TLR) activation and antiviral gene expression, including production of RANTES and interferon-beta (IFNbeta). The mechanism of this activation in rheumatoid synovial tissue is unknown. This study was designed to investigate the role of the IKK-related kinase IKKepsilon and IFN regulatory factor 3 (IRF-3) in the activation of antiviral genes in rheumatoid arthritis (RA).

Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) causes a symmetric, inflammatory polyarthritis that results in joint destruction and significant disability. Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in its pathogenesis and represent potential therapeutic targets. The IkappaB kinase (IKK)-related kinase, IKKepsilon/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by cultured fibroblast-like synoviocytes (FLS) and could participate in the pathogenesis of RA.

Signal transduction in rheumatoid arthritis.

Purpose: Signal transduction pathways are the intracellular mechanism by which cells respond and adapt to environmental stress. Understanding the critical networks in diseases like rheumatoid arthritis can potentially identify novel therapeutic targets.

Recent Findings: Dissecting the complex pathways involved in rheumatoid synovitis, including mitogen-activated protein kinases, NF-kB, tumor suppressors, Janus kinases, the signal transducer and activator of transcription, suppressors of cytokine stimulation, and toll-like receptors may lead to new approaches to inflammatory arthritis.

Identification of a novel Fc gamma RIIIa alpha-associated molecule that contains significant homology to porcine cathelin.

The following studies are the first to demonstrate the association of porcine FcgammaRIIIaalpha with a molecule that contains significant homology to the cathelin family of antimicrobial proteins. We performed immunoprecipitation of the porcine FcgammaRIIIaalpha multisubunit complex from Brij 96 lysates of polymorphonuclear leukocytes using the G7 mAb, which binds to FcgammaRIIIaalpha on the surface of porcine NK cells and phagocytes. Previous results indicate that the transmembrane alpha subunit of the FcgammaRIIIa complex is associated with the gamma subunit on the surface of porcine polymorphonuclear leukocytes and with several other unique proteins that surface iodinate and migrate at approximately 15, 20, and 25 kDa when analyzed by reducing SDS-PAGE.

Rheumatoid arthritis: regulation of synovial inflammation.

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disorder that presents as a symmetric polyarthritis associated with swelling and pain in multiple joints, often initially occurring in the joints of the hands and feet. Articular inflammation causes activation and proliferation of the synovial lining, expression of inflammatory cytokines, chemokine-mediated recruitment of additional inflammatory cells, as well as B cell activation with autoantibody production. A vicious cycle of altered cytokine and signal transduction pathways and inhibition of programmed cell death contribute to synoviocyte and osteoclast mediated cartilage and bone destruction.