IL-13 overexpression during immune complex arthritis diminishes MMP-mediated VDIPEN expression

We recently found that overexpression of the Th1 cytokine IFN-γ during immune complex arthritis (ICA) resulted in deterioration of matrix metalloproteinase (MMP)-mediated VDIPEN expression. On the contrary, overexpression of a Th2 cytokine might protect against cartilage destruction.

The aim of the study was to investigate whether local overexpression of the Th2 cytokine IL13 by gene transfer is able to diminish MMP-mediated VDIPEN expression during ICA and, if so, what mechanism is involved.

Human IL-13 (hIL-13) was locally overexpressed in the knee joint using an adenovirus (AdhIL13) and hIL-13 was detected in synovial washouts after 1, 2, 3, and 7 days. ICA was induced in C57Bl/6 by ia injection of lysozyme–antilysozyme complexes 1 day after AdhIL13 injection. Histology and synovium specimens were taken at days 1, 3 and 7 after ICA onset. Joint inflammation and MMP-mediated VDIPEN expression were determined. mRNA levels of MMP-3, MMP-12, and MMP-13 were detected in the synovium by Q-PCR.

AdhIL13 injected in naïve knee joints results in 1000 pg/ml hIL-13 after 1 day, and increased to 3000 pg/ml detected at days 2, 3 and 7. Surprisingly, IL-13 did not diminish joint inflammation, because the influx of inflammatory cells was similar in the Addel70 and AdhIL13 group. MMP-mediated VDIPEN expression was not found 1 day after ICA onset because of the early time point. At day 3, IL-13 overexpression resulted in a twofold reduction in VDIPEN expression and a threefold reduction at day 7, compared with the control group. This decrease might be the result of a declined production of MMPs. However, the mRNA level of MMP-3 was comparable between the two groups, whereas MMP-12 and MMP-13 mRNA levels were three times higher in the IL-13 group.

IL-13 overexpression during ICA does not alter the inflammatory response. VDIPEN expression was decreased, but this was not reflected by declined MMP production, suggesting that IL-13 interferes at the level of activation of pro-MMPs.

Affiliations

1. Department of Rheumatology, UMC Nijmegen, The Netherlands
   • KC Nabbe
   • , PL van Lent
   • , AE Holthuysen
   •  & WB van den Berg
2. Department of Medicine, UMS Chicago, USA
   • AE Koch

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