Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation |
| |
Authors: | Karin?CAM?Nabbe Email author" target="_blank">Peter?LEM?van LentEmail author Astrid?EM?Holthuysen Annet?W?Slo?tjes Alisa?E?Koch Timothy?RDJ?Radstake Wim?B?van den Berg |
| |
Institution: | (1) Department of Experimental Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands;(2) University of Michigan Medical School, Ann Arbor, Michigan, USA;(3) Veterans Administration Ann Arbor, Ann Arbor, Michigan, USA |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|