Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation

Arthritis Research & Therapy

Wim B van den Berg²  Timothy RDJ Radstake²  Alisa E Koch¹  Annet W Sloëtjes²  Astrid EM Holthuysen²  Peter LEM van Lent²  Karin CAM Nabbe² 

[1]University of Michigan Medical School, Ann Arbor, Michigan, USA

[2] and Veterans Administration Ann Arbor, Ann Arbor, Michigan, USA

[3]Department of Experimental Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands

关键词: MMPs;    Fcγ receptors;    interleukin-13;    experimental arthritis;    cartilage destruction;   

Others  :  1101097
DOI  :  10.1186/ar1502

 received in 2004-07-29, accepted in 2004-12-22,  发布年份 2005

【 摘 要 】

During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcγ receptors (FcγRs) (mainly FcγRI), cytokines (e.g. IL-1), and enzymes (matrix metalloproteinases (MMPs)). IL-13, a T helper 2 (Th2) cytokine abundantly found in synovial fluid of patients with rheumatoid arthritis, has been shown to reduce joint inflammation and bone destruction during experimental arthritis. However, the effect on severe cartilage destruction has not been studied in detail. We have now investigated the role of IL-13 in chondrocyte death and MMP-mediated cartilage damage during ICA. IL-13 was locally overexpressed in knee joints after injection of an adenovirus encoding IL-13 (AxCAhIL-13), 1 day before the onset of arthritis; injection of AxCANI (an empty adenoviral construct) was used as a control. IL-13 significantly increased the amount of inflammatory cells in the synovial lining and the joint cavity, by 30% to 60% at day 3 after the onset of ICA. Despite the enhanced inflammatory response, chondrocyte death was diminished by two-thirds at days 3 and 7. The mRNA level of FcγRI, a receptor shown to be crucial in the induction of chondrocyte death, was significantly down-regulated in synovium. Furthermore, MMP-mediated cartilage damage, measured as neoepitope (VDIPEN) expression using immunolocalization, was halved. In contrast, mRNA levels of MMP-3, -9, -12, and -13 were significantly higher and IL-1 protein, which induces production of latent MMPs, was increased fivefold by IL-13. This study demonstrates that IL-13 overexpression during ICA diminished both chondrocyte death and MMP-mediated VDIPEN expression, even though joint inflammation was enhanced.

【 授权许可】

   
2005 Nabbe et al.; licensee BioMed Central Ltd.

【 图 表 】

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