The last few years have seen the emergence of a novel superfamily of cytokines that display proinflammatory activities. These cytokines include platelet factor 4, beta-thromboglobulin, macrophage inflammatory proteins (MIP-1alpha, -1beta), RANTES, I-309, IL-8, monocyte chemoattractant protein (MCP-1), and gro. Some of these (I-309, RANTES) are produced exclusively by T lymphocytes, whereas others (MIP-1, IL-8, gro, MCP-1) are produced by a broader spectrum of cells. Most of these molecules have been shown to be chemotactic and activating factors for monocytes and neutrophils. IL-8 has been most extensively studied, and has been shown to be expressed at high levels by synovial fluid mononuclear cells of patients with rheumatoid arthritis. We have identified one member of this cytokine family, I-309, that is produced upon secondary stimulation of T lymphocytes in vitro, and that is specifically chemotactic for human monocytes. We propose to investigate the possibility that I-309 and related inflammatory cytokines play a role in the inflammatory process in rheumatoid arthritis. We will assess the relative expression and inducibility of the entire set of cytokines in peripheral blood and synovial fluid mononuclear cell samples, in synovial fibroblast cultures, in synovial tissue sections, and in synovial fluid, using a combination of quantitative PCR, Northern blots, in situ hybridization, indirect immunofluorescence and radioimmunoassay. We will address the relative contributions of various cytokines to chemotactic activity displayed by synovial fluid. We will test biologically active recombinant I-309 protein in in vitro experiments as a model monocyte activator to investigate the effects of such molecules on synovial mononuclear cells. We will complement these studies with parallel experiments in vivo which will determine the effects of recombinant I-309 on cellular infiltration and the elaboration of cytokines and adhesion molecules within human synovial tissue grafts in SCID mice.
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