Abstract
IntroductionThe first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis.MethodsWe studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)).ResultsIFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA.ConclusionsEarly therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis.
Highlights
The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA)
IFN-γ inhibits IL-1β induced matrix metalloproteinases (MMP) secretion by RA fibroblast-like synoviocytes (FLS) In RA cartilage damage is predominantly mediated by the MMPs; most notably MMP-1, -13 and -3 [19]
We studied IFN-γ's capacity to modulate IL-1β-induced MMP production by RA FLS
Summary
The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Interferon-γ (IFN-γ) is traditionally regarded as a proinflammatory cytokine by virtue of its strong macrophageactivating potential and its association with Th1 driven immune responses. This view is predominantly derived from in vitro observations at the cellular level. This belief has no doubt contributed to our over-simplified understanding of major human autoimmune disorders such as rheumatoid arthritis (RA), multiple sclerosis and insulin-dependent diabetes mellitus and guided the development of therapeutic strategies for these diseases for over two decades. In the cohort of patients who went on to developed RA, a broad range of T-cell, macrophage and stromal cell related cytokines were elevated in synovial fluid samples; how-
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