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Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor β chain prevents disease progression in experimental arthritis.

Zhang T, Bai X, Mao X - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Ministry of Education for Developmental Genes and Human Diseases, School of Life Sciences, Southeast University, Nanjing, China.

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.

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Therapeutic effects of PEI/IL-2/15Rβ siRNA complexes on AA rats.Male Wistar rats (n = 6 per group) were given Freund's complete adjuvant in the left hind footpad on day 0. IL-2/15Rβ siRNA-5 polyplexes were intravenously administered on days 10, 17, and 24 at 0.3 mg siRNA/kg. The rats receiving NC siRNA polyplexes or PBS were served as controls. (A) Arthritis score. Values are the mean and SD. *P<0.05; **P<0.01, versus the PBS group. (B) Representative histopathologies of the right hind ankle joints stained with hematoxylin and eosin (H&E). On day 31, rats were sacrificed and subjected to histopathological examination. Minimal articular inflammation and joint destruction were observed in the group treated with IL-2/15Rβ siRNA polyplexes, whereas PBS- and NC siRNA-treated rats exhibited pronounced synovial hyperplasia, bone damage and joint space narrowing. (C) Representative radiographs of right hind paws (n = 3 per group). On day 31, the rats were anaesthetized and subjected to radiography. Neither paw swelling nor joint damage was observed in normal rats. Severe bone erosion was seen in AA rats treated with either PBS or NC siRNA polyplexes, but the damage was much less in rats treated with IL-2/15Rβ siRNA polyplexes. (D) Effects of IL-2/15Rβ siRNA polyplexes on mRNA expression of inflammatory factors. At the end of the experiment (day 31), RNA was prepared from the right hind ankle joints of AA rats in each group. mRNA levels of each factor were determined by qPCR, normalized against GAPDH, and expressed as percentage of the PBS control. The result is presented as values (the mean and SD) obtained from three different samples randomly selected in each group. *P<0.05, versus PBS control.
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pone-0078619-g005: Therapeutic effects of PEI/IL-2/15Rβ siRNA complexes on AA rats.Male Wistar rats (n = 6 per group) were given Freund's complete adjuvant in the left hind footpad on day 0. IL-2/15Rβ siRNA-5 polyplexes were intravenously administered on days 10, 17, and 24 at 0.3 mg siRNA/kg. The rats receiving NC siRNA polyplexes or PBS were served as controls. (A) Arthritis score. Values are the mean and SD. *P<0.05; **P<0.01, versus the PBS group. (B) Representative histopathologies of the right hind ankle joints stained with hematoxylin and eosin (H&E). On day 31, rats were sacrificed and subjected to histopathological examination. Minimal articular inflammation and joint destruction were observed in the group treated with IL-2/15Rβ siRNA polyplexes, whereas PBS- and NC siRNA-treated rats exhibited pronounced synovial hyperplasia, bone damage and joint space narrowing. (C) Representative radiographs of right hind paws (n = 3 per group). On day 31, the rats were anaesthetized and subjected to radiography. Neither paw swelling nor joint damage was observed in normal rats. Severe bone erosion was seen in AA rats treated with either PBS or NC siRNA polyplexes, but the damage was much less in rats treated with IL-2/15Rβ siRNA polyplexes. (D) Effects of IL-2/15Rβ siRNA polyplexes on mRNA expression of inflammatory factors. At the end of the experiment (day 31), RNA was prepared from the right hind ankle joints of AA rats in each group. mRNA levels of each factor were determined by qPCR, normalized against GAPDH, and expressed as percentage of the PBS control. The result is presented as values (the mean and SD) obtained from three different samples randomly selected in each group. *P<0.05, versus PBS control.

Mentions: To evaluate the in vivo efficacy of silencing IL-2/15Rβ for RA treatment, AA rats were intravenously injected with PEI/IL-2/15Rβ siRNA once per week for three weeks. Compared with phosphate-buffered saline (PBS) and NC siRNA control groups, administration of IL-2/15Rβ siRNA nanoparticles significantly reduced clinical signs of arthritis, as assessed by paw swelling and arthritis scores (Figure 5A). The maximum effect was observed at the end of the observation period. To objectively measure the extent of joint destruction, rats were subjected to radiography on day 31, then killed, and paws were isolated for histological evaluation of the ankle joints. Histological and radiographic examination confirmed these findings, showing that the reductions in synovial tissue inflammation and in cartilage/bone destruction were striking in the group treated with IL-2/15Rβ siRNA (Figures 5B, C).


Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor β chain prevents disease progression in experimental arthritis.

Zhang T, Bai X, Mao X - PLoS ONE (2013)

Therapeutic effects of PEI/IL-2/15Rβ siRNA complexes on AA rats.Male Wistar rats (n = 6 per group) were given Freund's complete adjuvant in the left hind footpad on day 0. IL-2/15Rβ siRNA-5 polyplexes were intravenously administered on days 10, 17, and 24 at 0.3 mg siRNA/kg. The rats receiving NC siRNA polyplexes or PBS were served as controls. (A) Arthritis score. Values are the mean and SD. *P<0.05; **P<0.01, versus the PBS group. (B) Representative histopathologies of the right hind ankle joints stained with hematoxylin and eosin (H&E). On day 31, rats were sacrificed and subjected to histopathological examination. Minimal articular inflammation and joint destruction were observed in the group treated with IL-2/15Rβ siRNA polyplexes, whereas PBS- and NC siRNA-treated rats exhibited pronounced synovial hyperplasia, bone damage and joint space narrowing. (C) Representative radiographs of right hind paws (n = 3 per group). On day 31, the rats were anaesthetized and subjected to radiography. Neither paw swelling nor joint damage was observed in normal rats. Severe bone erosion was seen in AA rats treated with either PBS or NC siRNA polyplexes, but the damage was much less in rats treated with IL-2/15Rβ siRNA polyplexes. (D) Effects of IL-2/15Rβ siRNA polyplexes on mRNA expression of inflammatory factors. At the end of the experiment (day 31), RNA was prepared from the right hind ankle joints of AA rats in each group. mRNA levels of each factor were determined by qPCR, normalized against GAPDH, and expressed as percentage of the PBS control. The result is presented as values (the mean and SD) obtained from three different samples randomly selected in each group. *P<0.05, versus PBS control.
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Related In: Results  -  Collection

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pone-0078619-g005: Therapeutic effects of PEI/IL-2/15Rβ siRNA complexes on AA rats.Male Wistar rats (n = 6 per group) were given Freund's complete adjuvant in the left hind footpad on day 0. IL-2/15Rβ siRNA-5 polyplexes were intravenously administered on days 10, 17, and 24 at 0.3 mg siRNA/kg. The rats receiving NC siRNA polyplexes or PBS were served as controls. (A) Arthritis score. Values are the mean and SD. *P<0.05; **P<0.01, versus the PBS group. (B) Representative histopathologies of the right hind ankle joints stained with hematoxylin and eosin (H&E). On day 31, rats were sacrificed and subjected to histopathological examination. Minimal articular inflammation and joint destruction were observed in the group treated with IL-2/15Rβ siRNA polyplexes, whereas PBS- and NC siRNA-treated rats exhibited pronounced synovial hyperplasia, bone damage and joint space narrowing. (C) Representative radiographs of right hind paws (n = 3 per group). On day 31, the rats were anaesthetized and subjected to radiography. Neither paw swelling nor joint damage was observed in normal rats. Severe bone erosion was seen in AA rats treated with either PBS or NC siRNA polyplexes, but the damage was much less in rats treated with IL-2/15Rβ siRNA polyplexes. (D) Effects of IL-2/15Rβ siRNA polyplexes on mRNA expression of inflammatory factors. At the end of the experiment (day 31), RNA was prepared from the right hind ankle joints of AA rats in each group. mRNA levels of each factor were determined by qPCR, normalized against GAPDH, and expressed as percentage of the PBS control. The result is presented as values (the mean and SD) obtained from three different samples randomly selected in each group. *P<0.05, versus PBS control.
Mentions: To evaluate the in vivo efficacy of silencing IL-2/15Rβ for RA treatment, AA rats were intravenously injected with PEI/IL-2/15Rβ siRNA once per week for three weeks. Compared with phosphate-buffered saline (PBS) and NC siRNA control groups, administration of IL-2/15Rβ siRNA nanoparticles significantly reduced clinical signs of arthritis, as assessed by paw swelling and arthritis scores (Figure 5A). The maximum effect was observed at the end of the observation period. To objectively measure the extent of joint destruction, rats were subjected to radiography on day 31, then killed, and paws were isolated for histological evaluation of the ankle joints. Histological and radiographic examination confirmed these findings, showing that the reductions in synovial tissue inflammation and in cartilage/bone destruction were striking in the group treated with IL-2/15Rβ siRNA (Figures 5B, C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Ministry of Education for Developmental Genes and Human Diseases, School of Life Sciences, Southeast University, Nanjing, China.

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.

Show MeSH
Related in: MedlinePlus