Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor β chain prevents disease progression in experimental arthritis.
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.
Key Laboratory of Ministry of Education for Developmental Genes and Human Diseases, School of Life Sciences, Southeast University, Nanjing, China.
Tiantian
T
Zhang
Xuehua
X
Bai
Xiaohua
X
Mao
D061605:Administration, Intravenous; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D004337:Drug Carriers; D020868:Gene Silencing; D006614:Hindlimb / Q000276:immunology / Q000473:pathology; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D004337:Drug Carriers; D019409:Interleukin-15; D053583:Interleukin-1beta; D053646:Interleukin-2 Receptor beta Subunit; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D011094:Polyethyleneimine