Statistics from Altmetric.com
We have previously reported that anti-CII-containing immune complexes (anti-CII IC) induced production of tumour necrosis factor (TNF) β, interleukin (IL)1α and IL8 from monocytes via FcγRIIa.1 We have also shown that high levels of anti-CII were associated with IC-induced production of pro-inflammatory cytokines in vitro and increased laboratory signs of inflammation 2 and increased radiological erosions at the time of diagnosis. 3 The objective of this study was to establish an in vitro model that might explain the association between early joint destruction and the appearance of anti-CII in patients with early rheumatoid arthritis (RA). This RA pannus tissue model utilises IC-containing anti-CII antibodies as a stimulus and monocytes and synovial fibroblasts as responder cells.
Peripheral blood mononuclear cells (PBMC) and RA synovial fibroblasts (RASF) were stimulated with IC individually as well as in co-cultures. Monocytes were depleted to define the responder cells and TNFα and IL1β were neutralised to study the effect of the individual cytokines on MMP production. TNFα, IL1β, matrix metalloproteinase (MMP)-1, MMP-8 and MMP-13 were measured in cell culture supernatants using ELISA.
Anti-CII-containing IC induced production of TNFα, IL1β and MMP-1 in PBMC cultures and TNFα, IL1β, MMP-1 and MMP-8 in PBMC/fibroblast co-cultures in a dose-dependent manner. IC-induced MMP-1 responses were stronger and more associated with induced production of IL1β compared with MMP-8 responses. Baseline production of IL1β and MMP-1 increased significantly in co-cultures compared with individual cultures, whereas these effects were not observed for TNFα and MMP-8. Monocyte depletion decreased TNFα, IL1β and MMP-1 production, while the effect on MMP-8 production was variable. Cytokine neutralisation revealed that IL1β was a stronger inducer of MMP-1 than was TNFα. No production of MMP-13 was found in any cell cultures.
Synergistic actions between RASF and PBMC resulted in enhanced anti-CII IC-induced production of IL1β and MMP-1. IL1β and MMP-1 are regulated in parallel as anti-CII IC-induced IL1β supports the production of MMP-1. MMP-8 seems to be regulated by other means. Anti-CII IC-induced TNFα seems to be inferior to IL1β concerning MMP-1 induction. The fact that anti-CII IC stimulated synovial macrophages and fibroblasts to produce MMP, which are the first enzymes to cleave the interstitial collagens, may explain the anti-CII-associated joint destruction apparent in early RA.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.