Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: Interleukin-17 expression is upregulated in early disease

Abstract

SUMMARYThe aim of this study was to understand the immune processes controlling the initiation and spontaneous resolution of adjuvant arthritis (AA). We investigated synovial T-cell recruitment and mRNA expression of IL-17 and other important disease related cytokines, IFN-g , IL-2, IL-4, TNF and TGF-b in inguinal lymph node (ILN) and synovial membrane (SM). Arthritis severity was assessed by a numerical rating score and rats were sacrificed every 3±4 days postadjuvant induction. Further assessment involved quantitative radiology and histology of the ankle joints on each day, and the ILN and SM were removed for RNA extraction. Cytokine mRNA expression was measured using RT-PCR and densitometry. Paraffin sections of rat ankle joints were stained for T-cells (CD3) by immunohistochemistry. In the ILN, there was an increase in IL-17, TNF and IFN-g expression in the early stages of disease, with a secondary sustained increase in IFN-g expression. In the SM, there was expression of T-cell cytokines in early arthritis (day 13), and prolonged TNF and TGF-b expression, which reflected disease progression. IL-4 mRNA expression increased in the later stages of AA. Synovial T-cell numbers transiently increased at day 6, and remained high from days 13±28. Increased pro-inflammatory cytokine expression, including IL-17, in the ILN reflects the initiating events in the early stage of disease. IL-17 may therefore play an important role in the pathogenesis of AA. The increase in IL-4 (an antiinflammatory cytokine) in the SM in the later stages of AA suggests that IL-4 is involved in the spontaneous resolution of AA. The initial increase in IFN-g in the ILN may reflect a pro-inflammatory response, while the prolonged secondary increase may indicate activation of regulatory T-cells.

Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

“…In this study, we describe that IFN-γ is associated with protection against adjuvant arthritis (AA), which is considered to be a Th1-mediated disease. Our results validate and further enlarge the scope and implications of observations reported earlier in the AA model [23,24].…”

Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: A two‐year prospective study (the DAMAGE study cohort)

“…This finding supports the reported findings of in vitro studies showing that IFN␥ has a potent negative effect on RANKL-induced osteoclastogenesis by degrading the RANK adapter protein TNF receptor-associated factor 6 (31). Other explanations also include the finding that in adjuvant arthritis, inhibition of IFN␥ in later disease exacerbates the disease, and our previous work shows high levels of synovial IFN␥ expression in this phase (32). Similar results are found in the immune-mediated model of experimental allergic encephalomyelitis, and it has been hypothesized that this reflects T regulatory cell activity (33).…”

Immune response to gut Escherichia coli and susceptibility to adjuvant arthritis in the rats

“…It is possible that the percentage of positive cells would differ between the groups in other time points. It is well established that the expression of pro-infl ammatory cytokines (TNF, IFN-γ, IL-2 and IL-17) increases in the inguinal lymph nodes in the early stages of AA [37]. The expression of these cytokines is transient, with the exception of IFN-γ, showing secondary growth later in the course of the disease (from day 17 onwards).…”

“…The expression of these cytokines is transient, with the exception of IFN-γ, showing secondary growth later in the course of the disease (from day 17 onwards). Also, it was suggested that the initial increase in IFN-γ occurs within pro-infl ammatory response and that the subsequent increase may refl ect the activation of regulatory T cells [37]. Thus, it is possible that even at the peak of the disease, a signifi cant change in the population of T cells might be taking place; it is only that within the limited time period available we might have missed the narrow window of opportunity to detect these subtle differences between the experimental groups.…”