Dysregulation of interleukin‐10–dependent gene expression in rheumatoid arthritis synovial macrophages

Abstract

Objective. The inflammatory cytokines tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL-10 is a potent antiinflammatory cytokine that suppresses macrophage TNF␣ and IL-1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL-10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL-10-inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages.Methods. Macrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL-10 or interferon-␥ (IFN␥). Gene expression was analyzed using Affymetrix microarrays and protocols. Real-time polymerase chain reaction was used to confirm changes in gene expression.Results. The number of genes induced by IL-10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL-10 stimulation was qualitatively altered, such that IL-10 preferentially increased expression of IFN␥-inducible genes. In contrast, arthritic macrophages expressed many IFN␥-inducible genes prior to stimulation, and their response to IFN␥ remained mostly intact.Conclusion. These results demonstrate that IL-10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL-10, with attenuation of its antiinflammatory function and a concomitant retention of IFN␥-like activating functions, provides a basis for the lack of efficacy of IL-10 in suppressing inflammatory arthritis.

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

“…Consistent with this, macrophages derived from the peripheral blood monocytes of AS patients were reported to have an impaired IFN␥ signature as compared with that in healthy controls, which could be restored in vitro by incubation with IFN␥ (35). Macrophages isolated from RA SF were reported to have an opposite profile, with a strong IFN␥ signature and a broad resistance to the effects of IL-10, one of the major factors for M2 polarization (36,37).…”

Evaluation of inflammation and oxidative stress in ankylosing spondylitis: a role for macrophage migration inhibitory factor

“…To date, there have been no published reports of MIF levels in AS. In contrast, IL-10, which is a potent anti-inflammatory cytokine through its suppressive action on macrophage TNF-a and IL-1 production, has been suggested to act as an inflammatory mediator in inflammatory diseases such as RA and AS [10]. IL-10 has also been reported to reduce the production of MIF from T cells and abolish recombinant MIF-mediated migration inhibition of human monocytes [11].…”

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

“…Indeed, 11βHSD1 is induced in human monocytes upon differentiation to macrophages [27]. 11βHSD1 expression was induced by the anti-inflammatory IL-10 in synovial macrophages from control patients, but not in macrophages from RA patients [28]. In addition, CD163- cells, typically activated macrophages, but not CD3+ lymphocytes or prolyl 4-hydroxylase-positive fibroblasts, expressed 11βHSD1 [26].…”