Abstract
The role of interleukin (IL)-15 in the pathogenesis of rheumatoid arthritis (RA) is well established; however, systemic knockdown of IL-15 receptor (IL-15R) for reduction in inflammation at local sites has not been demonstrated. In this study, the therapeutic effect of intravenously administered siRNA targeting the β chain of IL-15R which is shared by the receptor for IL-2 was examined in rats with adjuvant-induced arthritis (AA). Polyethylenimine (PEI)-complexed siRNA nanoparticles could easily accumulate in arthritic paws of AA rats. In the paws, the nanoparticles were avidly taken up by macrophages and to a lesser extent by T cells. Weekly administered IL-2/15Rβ siRNA polyplexes were capable of decreasing disease progression in AA rats, with striking inhibition of clinical, radiologic, and histologic features of RA. The observed therapeutic effect was associated with reduced expression of proinflammatory mediators in the inflamed joints. Thus, this study provides evidence that IL-2/15Rβ could be targeted for the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and persistent inflammation that is recognized to result from the interaction among macrophages, T cells, B cells, and nonhematopoietic cells such as fibroblasts
Since cc is shared by receptors for IL-4, IL-7, IL-9, IL-15, and IL-21 and a loss of cc function causes immunodeficiencies in both humans and mice [18], it is anticipated that knockdown of cc may lead to severe systemic side effects
Peritoneal macrophages were transfected with each of the six siRNA duplexes and the silencing of IL-2/15Rb mRNA was measured by quantitative RT-PCR
Summary
Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and persistent inflammation that is recognized to result from the interaction among macrophages, T cells, B cells, and nonhematopoietic cells such as fibroblasts These interactions are facilitated by the actions of cytokines released from the activated cells that through both autocrine and paracrine mechanisms, induce the production of other proinflammatory cytokines, which together contribute to the pathogenesis of this disease and lead to joint damage [1,2]. In RA, IL-15 is expressed primarily by macrophages as well as by fibroblast-like synoviocytes and endothelial cells [5] It exhibits pleiotropic proinflammatory effects on numerous target cell types relevant to a variety of inflammatory conditions [6] and was thought to be at the apex of the cytokine cascade created in the inflamed joints [7]. In support of this view, several IL-15- or IL-15 receptor (IL-15R)-directed monoclonal antibodies and fusion proteins have been effective in ameliorating RA in animal models [13,14,15]
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