Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation.
During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcgamma receptors (FcgammaRs) (mainly FcgammaRI), 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 FcgammaRI, 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.
Nabbe
Karin C A M
KC
Department of Experimental Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. k.nabbe@reuma.umcn.nl
van Lent
Peter L E M
PL
Holthuysen
Astrid E M
AE
Sloëtjes
Annet W
AW
Koch
Alisa E
AE
Radstake
Timothy R D J
TR
van den Berg
Wim B
WB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000473:pathology*; D016923:Cell Death; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D019902:Chondrocytes / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D007105:Immune Complex Diseases / Q000473:pathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D007719:Knee Joint; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000096:biosynthesis* / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism; D014161:Transduction, Genetic
D018925:Chemokines; C485701:Fcgr1 protein, mouse; D007375:Interleukin-1; D018793:Interleukin-13; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C093378:peptide VDIPEN; D020782:Matrix Metalloproteinases
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