Deficient expression of interleukin‐10 receptor α chain in rheumatoid arthritis synovium: Limitation of animal models of inflammation

Neidhart, Michel; Jüngel, Astrid; Ospelt, Caroline; Michel, Beat A.

doi:10.1002/art.21274

Cited by 19 publications

(15 citation statements)

References 12 publications

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“…Normal levels of circulating Tregs and normal expression of IL-10R on circulating CD4 + T lymphocytes did not explain the strong production of IFN-γ and TNF-α and lesion development in CL patients [1, 6]. It has been shown that decreased IL-10R expression is associated with exaggerated pro-inflammatory responses in rheumatoid arthritis [18] because cells do not properly respond to IL-10-mediated suppression. However, altered IL-10R expression levels also did not support our first hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of regulatory T cell (Treg) function in patients infected with Leishmania braziliensis

et al. 2013

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Th1 immune responses are crucial for eliminating Leishmania parasites. However, despite strong Th1 responses, cutaneous leishmaniasis (CL) patients infected with L. braziliensis develop the disease, while milder Th1 responses are found in sub-clinical (SC) infections. Therefore, CL patients may experience impaired regulatory T cell (Treg) function, causing excessive Th1 responses and tissue damage. To address this hypothesis, we characterized the function of circulating Tregs in L. braziliensis infected CL patients and compared them to Tregs from uninfected controls (UC) and SC subjects. The frequency of circulating Tregs was similar in CL patients, UC and SC subjects. Moreover, CL patients Tregs suppressed lymphocyte proliferation and PBMC pro-inflammatory cytokine production more efficiently than UC Tregs, and also produced higher levels of IL-10 than UC and SC Tregs. Furthermore, PBMC and mononuclear cells from lesions of CL patients responded normally to Treg-induced suppression. Therefore, the lesion development in CL patients infected with L. braziliensis is not associated with impairment in Treg function or failure of cells to respond to immunomodulation. Rather, the increased Treg activation in CL patients may impair parasite elimination, resulting in establishment of chronic infection. Thus, immunological strategies that interfere with this response may improve leishmaniasis treatment.

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Section: Discussionmentioning

confidence: 99%

Characterization of regulatory T cell (Treg) function in patients infected with Leishmania braziliensis

et al. 2013

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“…However, the concept needs to be tested in human RA, as the role of IL-10 in RA patients is far from clarified: RA patients have significantly elevated levels of IL-10 in synovial fluid [32] while the expression of IL-10 receptors are reduced in synovial tissue [33] compared with osteoarthritic controls, and treatment with systemic recombinant IL-10 in human RA patients has so far not shown any convincing results [34]. Although these findings appear disappointing they do not contradict our data.…”

Section: Discussionmentioning

confidence: 99%

Disease-Dependent Local IL-10 Production Ameliorates Collagen Induced Arthritis in Mice

et al. 2012

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Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease characterised by periods of flare and remission. Today’s treatment is based on continuous immunosuppression irrespective of the patient’s inflammatory status. When the disease is in remission the therapy is withdrawn but withdrawal attempts often results in inflammatory flares, and re-start of the therapy is commenced when the inflammation again is prominent which leads both to suffering and increased risk of tissue destruction. An attractive alternative treatment would provide a disease-regulated therapy that offers increased anti-inflammatory effect during flares and is inactive during periods of remission. To explore this concept we expressed the immunoregulatory cytokine interleukin (IL)-10 gene under the control of an inflammation dependent promoter in a mouse model of RA - collagen type II (CII) induced arthritis (CIA). Haematopoetic stem cells (HSCs) were transduced with lentiviral particles encoding the IL-10 gene (LNT-IL-10), or a green fluorescence protein (GFP) as control gene (LNT-GFP), driven by the inflammation-dependent IL-1/IL-6 promoter. Twelve weeks after transplantation of transduced HSCs into DBA/1 mice, CIA was induced. We found that LNT-IL-10 mice developed a reduced severity of arthritis compared to controls. The LNT-IL-10 mice exhibited both increased mRNA expression levels of IL-10 as well as increased amount of IL-10 produced by B cells and non-B APCs locally in the lymph nodes compared to controls. These findings were accompanied by increased mRNA expression of the IL-10 induced suppressor of cytokine signalling 1 (SOCS1) in lymph nodes and a decrease in the serum protein levels of IL-6. We also found a decrease in both frequency and number of B cells and serum levels of anti-CII antibodies. Thus, inflammation-dependent IL-10 therapy suppresses experimental autoimmune arthritis and is a promising candidate in the development of novel treatments for RA.

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“…First, exogenous IL‐10 used therapeutically was not effective in suppressing RA or seronegative SpA (9, 10), suggesting that IL‐10 did not suppress synovial TNFα and IL‐1 production. Second, IL‐10 activation of Stat3, which is required for suppression of TNFα and IL‐1 production, was diminished in RA synovial macrophages, as was IL‐10 receptor expression (19, 41). Third, IL‐10 did not induce expression of genes proposed to mediate IL‐10 suppression of TNFα production, such as heme oxygenase 1 and Bcl‐3 (42, 43), in arthritic macrophages.…”

Section: Discussionmentioning

confidence: 99%

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

Antoniv

Ivashkiv

2006

Arthritis & Rheumatism

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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.

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Deficient expression of interleukin‐10 receptor α chain in rheumatoid arthritis synovium: Limitation of animal models of inflammation

Cited by 19 publications

References 12 publications

Characterization of regulatory T cell (Treg) function in patients infected with Leishmania braziliensis

Characterization of regulatory T cell (Treg) function in patients infected with Leishmania braziliensis

Disease-Dependent Local IL-10 Production Ameliorates Collagen Induced Arthritis in Mice

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

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