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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intravenous
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Animals
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Arthritis, Experimental / immunology
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Arthritis, Experimental / pathology
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Arthritis, Experimental / therapy*
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Disease Progression
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Drug Carriers
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Gene Silencing
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Hindlimb / immunology
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Hindlimb / pathology
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Interleukin-15 / biosynthesis
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Interleukin-15 / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology
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Interleukin-2 Receptor beta Subunit / antagonists & inhibitors*
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Interleukin-2 Receptor beta Subunit / immunology
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Macrophages / immunology*
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Macrophages / pathology
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Male
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Molecular Targeted Therapy*
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Nanoparticles / chemistry
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Nanoparticles / metabolism
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Polyethyleneimine / chemistry
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Polyethyleneimine / metabolism
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RNA, Small Interfering / administration & dosage*
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Rats
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Rats, Wistar
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T-Lymphocytes / immunology*
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T-Lymphocytes / pathology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Drug Carriers
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Interleukin-15
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Interleukin-1beta
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Interleukin-2 Receptor beta Subunit
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RNA, Small Interfering
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Tumor Necrosis Factor-alpha
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Polyethyleneimine
Grants and funding
This study was supported by National Natural Science Foundation of China (81071445). The URL of the funder's website is
www.nsfc.gov.cn. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.