Local overexpression of adeno-viral IL-4 protects cartilage from metallo proteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs.
OBJECTIVE
To determine whether IL-4 protects against metalloproteinase-induced cartilage destruction during immune complex mediated arthritis and to elucidate its mechanism.


METHODS
Experimental immune complex arthritis (ICA) was raised by injecting lysozyme into the knee joints of mice which previously were given anti-lysozyme antibodies. Three days before ICA induction, mice were injected into the right knee joint with either IL-4 expressing or empty control recombinant human type 5 adenovirus. Joint inflammation and cartilage destruction (PG depletion, erosion) was measured by histology of total knee joints. Aggrecan breakdown in cartilage caused by metalloproteinases (MMPs) was studied by immunolocalization using anti-VDIPEN antibodies.


RESULTS
Four days after ICA induction, histological analysis showed comparable exudate and infiltrate in both groups. Depletion of proteoglycans as measured by loss of red staining was also comparable in both groups. IL-4 treatment inhibited MMP-mediated neoepitope expression by 90%. Moreover, cartilage matrix erosion was evident in all animals (10 out of 10 mice) in the control group and significantly diminished (only two out of ten mice) in the IL-4 treated group. Incubation of patellae with APMA, which activates latent MMPs resulted in VDIPEN expression which was not significantly different from control ICA indicating that comparable amounts of latent pro-MMPs are present in IL-4 treated arthritic knee joints.


CONCLUSIONS
This study indicates that during ICA, IL-4 largely prevents MMP-mediated aggrecan breakdown and severe cartilage erosion. IL-4 does not inhibit production of latent MMPs by the chondrocyte but predominantly interferes with its activation.
van Lent
P L E M
PL
Department of Rheumatology, University Medical Centre Nijmegen, The Netherlands. P.vanlent@reuma.azn.nl
Holthuysen
A E M
AE
Slöetjes
A
A
Lubberts
E
E
van den Berg
W B
WB
D000256:Adenoviridae; D053674:Aggrecans; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000517:prevention & control*; D002356:Cartilage / Q000276:immunology*; D019902:Chondrocytes / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005822:Genetic Vectors; D006614:Hindlimb; D015847:Interleukin-4 / Q000627:therapeutic use*; D007596:Joints; D037181:Lectins, C-Type; D008297:Male; D020782:Matrix Metalloproteinases / Q000276:immunology*; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins
C508320:Acan protein, mouse; D053674:Aggrecans; D018501:Antirheumatic Agents; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D011994:Recombinant Proteins; D015847:Interleukin-4; D020782:Matrix Metalloproteinases