IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflammation in the murine air pouch model

S. Yang, B. Wu, L. Mayton, Christopher H Evans, P. D. Robbins, P. H. Wooley

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Objective: This study examined anti-inflammatory gene therapy to ameliorate tissue responses to ultra high molecular weight polyethylene (UHMWPE) particles in the murine air pouch. Methods: Retroviruses encoding human interleukin-1 receptor antagonist (IL-1Ra), viral interleukin-10 (vIL-10), or LacZ (reporter) genes were injected into murine air pouches stimulated by UHMWPE particles. Pouch membranes and fluids were harvested at 1, 3 and 7 days post gene-transduction, and assayed for markers of inflammation using histological, molecular, and immunological techniques. Results: Real time RT-PCR and ELISA showed a strong production of IL-1β in pouch tissue and lavage fluid induced by particle stimulation, accompanied by a lower expression of IL-6, TNF-α and IL-4. Transduction of IL-1Ra or vIL-10 genes resulted in a significant reduction of IL-1β both at the mRNA and at the protein level. The gene therapy also resulted in diminution of IL-6 and TNF-α expression. In addition, significant elevation of TGF-β expression was observed in IL-1Ra transduced pouches. Histological analysis revealed that the membranes of pouches transduced with vIL-10 or IL-1Ra were significantly less inflamed than the membranes of non-viral and LacZ-transduced pouches, with less cellular proliferation and lowered monocyte/macrophage influx. Conclusions: IL-1Ra or vIL-10 gene transduction was effective in ameliorating local inflammation by reducing the IL-1 production and subsequent cellular events elicited in response to UHMWPE particles in this model. These findings suggest that IL-1 directed gene therapy might be excellent therapeutic candidates to prevent or retard the inflammatory response to wear debris that contributes to the pathology of aseptic loosening.

Original languageEnglish (US)
Pages (from-to)342-350
Number of pages9
JournalInflammation Research
Volume51
Issue number7
StatePublished - 2002
Externally publishedYes

Fingerprint

Gene transfer
Interleukin-1 Receptors
Interleukin-10
Interleukin-1
Gene therapy
Air
Inflammation
Genes
Genetic Therapy
Membranes
Interleukin-6
Tissue
Immunologic Techniques
Histological Techniques
Lac Operon
Fluids
Macrophages
Therapeutic Irrigation
Pathology
Retroviridae

Keywords

  • Gene transfer
  • IL-1Ra
  • Inflammation
  • vIL-10
  • Wear debris

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology (medical)
  • Immunology
  • Cell Biology

Cite this

IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflammation in the murine air pouch model. / Yang, S.; Wu, B.; Mayton, L.; Evans, Christopher H; Robbins, P. D.; Wooley, P. H.

In: Inflammation Research, Vol. 51, No. 7, 2002, p. 342-350.

Research output: Contribution to journalArticle

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abstract = "Objective: This study examined anti-inflammatory gene therapy to ameliorate tissue responses to ultra high molecular weight polyethylene (UHMWPE) particles in the murine air pouch. Methods: Retroviruses encoding human interleukin-1 receptor antagonist (IL-1Ra), viral interleukin-10 (vIL-10), or LacZ (reporter) genes were injected into murine air pouches stimulated by UHMWPE particles. Pouch membranes and fluids were harvested at 1, 3 and 7 days post gene-transduction, and assayed for markers of inflammation using histological, molecular, and immunological techniques. Results: Real time RT-PCR and ELISA showed a strong production of IL-1β in pouch tissue and lavage fluid induced by particle stimulation, accompanied by a lower expression of IL-6, TNF-α and IL-4. Transduction of IL-1Ra or vIL-10 genes resulted in a significant reduction of IL-1β both at the mRNA and at the protein level. The gene therapy also resulted in diminution of IL-6 and TNF-α expression. In addition, significant elevation of TGF-β expression was observed in IL-1Ra transduced pouches. Histological analysis revealed that the membranes of pouches transduced with vIL-10 or IL-1Ra were significantly less inflamed than the membranes of non-viral and LacZ-transduced pouches, with less cellular proliferation and lowered monocyte/macrophage influx. Conclusions: IL-1Ra or vIL-10 gene transduction was effective in ameliorating local inflammation by reducing the IL-1 production and subsequent cellular events elicited in response to UHMWPE particles in this model. These findings suggest that IL-1 directed gene therapy might be excellent therapeutic candidates to prevent or retard the inflammatory response to wear debris that contributes to the pathology of aseptic loosening.",
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T1 - IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflammation in the murine air pouch model

AU - Yang, S.

AU - Wu, B.

AU - Mayton, L.

AU - Evans, Christopher H

AU - Robbins, P. D.

AU - Wooley, P. H.

PY - 2002

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N2 - Objective: This study examined anti-inflammatory gene therapy to ameliorate tissue responses to ultra high molecular weight polyethylene (UHMWPE) particles in the murine air pouch. Methods: Retroviruses encoding human interleukin-1 receptor antagonist (IL-1Ra), viral interleukin-10 (vIL-10), or LacZ (reporter) genes were injected into murine air pouches stimulated by UHMWPE particles. Pouch membranes and fluids were harvested at 1, 3 and 7 days post gene-transduction, and assayed for markers of inflammation using histological, molecular, and immunological techniques. Results: Real time RT-PCR and ELISA showed a strong production of IL-1β in pouch tissue and lavage fluid induced by particle stimulation, accompanied by a lower expression of IL-6, TNF-α and IL-4. Transduction of IL-1Ra or vIL-10 genes resulted in a significant reduction of IL-1β both at the mRNA and at the protein level. The gene therapy also resulted in diminution of IL-6 and TNF-α expression. In addition, significant elevation of TGF-β expression was observed in IL-1Ra transduced pouches. Histological analysis revealed that the membranes of pouches transduced with vIL-10 or IL-1Ra were significantly less inflamed than the membranes of non-viral and LacZ-transduced pouches, with less cellular proliferation and lowered monocyte/macrophage influx. Conclusions: IL-1Ra or vIL-10 gene transduction was effective in ameliorating local inflammation by reducing the IL-1 production and subsequent cellular events elicited in response to UHMWPE particles in this model. These findings suggest that IL-1 directed gene therapy might be excellent therapeutic candidates to prevent or retard the inflammatory response to wear debris that contributes to the pathology of aseptic loosening.

AB - Objective: This study examined anti-inflammatory gene therapy to ameliorate tissue responses to ultra high molecular weight polyethylene (UHMWPE) particles in the murine air pouch. Methods: Retroviruses encoding human interleukin-1 receptor antagonist (IL-1Ra), viral interleukin-10 (vIL-10), or LacZ (reporter) genes were injected into murine air pouches stimulated by UHMWPE particles. Pouch membranes and fluids were harvested at 1, 3 and 7 days post gene-transduction, and assayed for markers of inflammation using histological, molecular, and immunological techniques. Results: Real time RT-PCR and ELISA showed a strong production of IL-1β in pouch tissue and lavage fluid induced by particle stimulation, accompanied by a lower expression of IL-6, TNF-α and IL-4. Transduction of IL-1Ra or vIL-10 genes resulted in a significant reduction of IL-1β both at the mRNA and at the protein level. The gene therapy also resulted in diminution of IL-6 and TNF-α expression. In addition, significant elevation of TGF-β expression was observed in IL-1Ra transduced pouches. Histological analysis revealed that the membranes of pouches transduced with vIL-10 or IL-1Ra were significantly less inflamed than the membranes of non-viral and LacZ-transduced pouches, with less cellular proliferation and lowered monocyte/macrophage influx. Conclusions: IL-1Ra or vIL-10 gene transduction was effective in ameliorating local inflammation by reducing the IL-1 production and subsequent cellular events elicited in response to UHMWPE particles in this model. These findings suggest that IL-1 directed gene therapy might be excellent therapeutic candidates to prevent or retard the inflammatory response to wear debris that contributes to the pathology of aseptic loosening.

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