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

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-1beta in pouch tissue and lavage fluid induced by particle stimulation, accompanied by a lower expression of IL-6, TNF-alpha and IL-4. Transduction of IL-1Ra or vIL-10 genes resulted in a significant reduction of IL-1beta both at the mRNA and at the protein level. The gene therapy also resulted in diminution of IL-6 and TNF-alpha expression. In addition, significant elevation of TGF-beta 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.

• Authors: S Yang, B Wu, L Mayton, C H Evans, P D Robbins, P H Wooley
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 51 Issue 7 Pg. 342-50 (Jul 2002) ISSN: 1023-3830 [Print] Switzerland
• PMID: 12146725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Cytokines
• IL1RN protein, human
• Il1rn protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Sialoglycoproteins
• Interleukin-10
• Polyethylene

Topics

• Air
• Animals
• Antibodies, Monoclonal
• Cell Count
• Cytokines (biosynthesis, genetics)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation (genetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Inflammation (pathology, prevention & control)
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-10 (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Molecular Weight
• Polyethylene
• Retroviridae (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sialoglycoproteins (biosynthesis, genetics)