Protective role of IFN-γ in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production

Kelchtermans, Hilde; Struyf, Sofie; Klerck, Bert De; Mitera, Tania; Alen, Marijke; Geboes, Lies; Balen, Maarten Van; Dillen, Chris; Put, Willy; Gysemans, Conny; Billiau, Alfons; Damme, Jozef Van; Matthys, Patrick

doi:10.1189/jlb.0806486

Cited by 43 publications

(38 citation statements)

References 64 publications

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“…Similarly, in other models such as experimental autoimmune encephalomyelitis and collagen-induced arthritis, IFN-␥ gene deletion or administration of anti-IFN-␥ antibodies leads to increased severity of disease (23,24).…”

Section: Discussionmentioning

confidence: 99%

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Sheikh

Matsuoka

Onyiah

et al. 2011

Journal of Biological Chemistry

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IL-23 is a heterodimeric cytokine composed of a p19 subunit (Il23a) and a p40 subunit (Il12b) also shared with IL-12. Il23a is expressed in macrophages and dendritic cells and is induced by microbial products such as LPS (1). The importance of IL-23 in the pathogenesis of chronic inflammatory disorders is supported by the recent identification of IL-23 receptor susceptibility alleles associated with the inflammatory bowel diseases, psoriasis, and spondyloartropathies (2). IL-23-driven inflammation has been linked to its role in the development and persistence of a pathogenic subset of Thelper type 17 (T H 17) cells (3).Recently, we demonstrated a protective role for IFN-␥, the signature T H 1 cytokine, in chronic intestinal inflammation through attenuation of Il23a gene expression (4). IFN-␥ receptor deficiency exacerbated IL-23-mediated colitis in IL-10-deficient (IL-10 Ϫ/Ϫ ) mice. Although the molecular regulation of IL-12 p35 (Il12a) and Il12b expression has been well studied, many important questions remain about Il23a regulation in macrophages (1).Toll-like receptors (TLRs) 2 induce Il23a expression in macrophages through recruitment of NF-B family members to binding sites in the proximal promoter (5). We demonstrated that IFN-␥ inhibited LPS-induced NF-B RelA while enhancing p50 subunit recruitment to the Il23a promoter (4). IFN-␥-mediated IL-23 inhibition was in striking contrast to its augmentation of LPS-induced IL-12 p40 and IL-12 p70 expression (4). Notably, TLR and IFN-␥ transcriptional response in the Il12a and Il12b promoters is mediated by interferon regulatory factor (IRF) family members (1). Specifically, mice deficient in IRF-1, IRF-2, and IRF-8 demonstrate defects in Il12a and Il12b production (6). The reciprocal regulation of IL-12 family members by IFN-␥ highlights its complex biological role in the maintenance of immune homeostasis.In these experiments, we functionally characterize an interferon-stimulated response element (ISRE) in the Il23a promoter. This ISRE mediated Il23a promoter induction by LPS and inhibition of LPS-induced activity by IFN-␥. LPS-and IFN-␥-induced IRF-1 is identified as a negative regulator of IL-23 in macrophages and experimental colitis. EXPERIMENTAL PROCEDURES Mice-WT, IL-10Ϫ/Ϫ , NF-B p50 Ϫ/Ϫ , and IRF-1 Ϫ/Ϫ mice on a C57BL/6 background were matched for age in all experiments. IRF-1/IL-10 Ϫ/Ϫ mice were obtained by crossing IL-10 Ϫ/Ϫ and IRF-1 Ϫ/Ϫ mice. Heterozygous offspring were then bred to obtain homozygous IL-10/IRF-1 Ϫ/Ϫ mice. Age-

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Section: Discussionmentioning

confidence: 99%

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Sheikh

Matsuoka

Onyiah

et al. 2011

Journal of Biological Chemistry

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“…Our data are also consistent with opposite roles of IFN-c and PGE 2 in tipping the balance between macrophages and neutrophils in RA. Recent reports suggest that one of the mechanisms through which IFN-c limits inflammation in the arthritic joint is not only by inhibiting the influx of neutrophils [32,33], but also by stimulating the influx of neutrophil-clearing macrophages into the joint [34]. Consistent with this, we show that IFN-c stimulates the release of multiple macrophage chemotactic factors and inhibits the release of IL-8, a major neutrophil chemokine, while PGE 2 and/or EP4 activation has opposite effects (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mutual antagonistic relationship between prostaglandin E₂ and IFN‐γ: Implications for rheumatoid arthritis

Mathieu¹,

Lord‐Dufour²,

Bernier³

et al. 2008

Eur J Immunol

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Prostaglandin E 2 (PGE 2 ) is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE 2 , acting through the EP4 receptor, has both pro-and anti-inflammatory roles in vivo. To shed light on this dual role of PGE 2 , we investigated its effects in whole blood and in primary human fibroblast-like synoviocytes (FLS). Gene expression analysis in human leukocytes, confirmed at the protein level, revealed an EP4-dependent inhibition of the expression of genes involved in the IFN-c-activation pathway, including IFN-c itself. This effect of the PGE 2 /EP4 axis on IFN-c is a reciprocal phenomenon since IFN-c blocks PGE 2 release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-c and PGE 2 extends to downstream cytokine and chemokine release; PGE 2 counters the effects of IFN-c, on the release of IP-10, IL-8, TNF-a and IL-1b. To gain further insight into IFN-c-mediated cellular events in RA, we assessed the effects of IFN-c on gene expression in FLS. We observed an IFN-c-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE 2 and IFN-c, which may represent a fundamental mechanism of immune control in diseases such as RA.

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“…Leucocyte chemotaxis Cell migration was evaluated using a classical chemotaxis assay [27,28]. Briefly, islets from Irf-1 −/− or control C57BL/6 mice were cultured for 3 days in serum-free synthetic medium, using BioWhittaker Ultraculture medium (Lonza, Verviers, Belgium), supplemented with GlutaMAX-I (Invitrogen), 100 U/ml penicillin and 100µg/ml streptomycin, in absence or presence of recombinant human IL-1β (50 U/ml) plus recombinant mouse IFN-γ (1,000 U/ml).…”

Section: Methodsmentioning

confidence: 99%

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

Gysemans¹,

Callewaert²,

Moore

et al. 2009

Diabetologia

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Aims/hypothesis IFN-γ, together with other inflammatory cytokines such as IL-1β and TNF-α, contributes to beta cell death in type 1 diabetes. We analysed the role of the transcription factor interferon regulatory factor (IRF)-1, a downstream target of IFN-γ/signal transducer and activator of transcription (STAT)-1, in immune-mediated beta cell destruction. Methods Islets from mice lacking Irf-1 (Irf-1 −/− ) and control C57BL/6 mice were transplanted in overtly diabetic NOD mice. Viability and functionality of islets were evaluated in vitro. Chemokine expression by Irf-1 −/− islets and INS-1E cells transfected with Irf-1 short interfering RNA (siRNA) was measured by real-time PCR as well as in functional assays in vitro. Results IRF-1 deletion in islets was associated with higher prevalence of primary non-function (63% vs 25%, p≤0.05) and shorter functioning graft survival (6.0±2.6 vs 10.4± 4.8 days, p≤0.05) in contrast to similar skin graft survival. Although Irf-1 −/− islets were resistant to cytokine-induced cell death, insulin secretion by them was lower than that of control C57BL/6 islets under medium and cytokine conditions. IL-1 receptor antagonist partly restored the cytokine-induced secretory defect in vitro and completely prevented primary non-function in vivo. Cytokine-exposed Irf-1 −/− islets and INS-1E cells transfected with Irf-1 siRNA showed increased expression of Mcp-1 (also known as Ccl2), Ip-10 (also known as Cxcl10), Mip-3α (also known as Ccl20) and Inos (also known as Nos2) mRNA and elevated production of monocyte chemoattractant protein-1 (MCP-1) and nitrite compared with controls. In vivo, Irf-1 −/− islets displayed a higher potential to attract immune cells, reflected by more aggressive immune infiltration in the grafted islets. Conclusions/interpretation These data indicate a key regulatory role for IRF-1 in insulin and chemokine secretion by pancreatic islets under inflammatory attack.

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Protective role of IFN-γ in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production

Cited by 43 publications

References 64 publications

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Mutual antagonistic relationship between prostaglandin E₂ and IFN‐γ: Implications for rheumatoid arthritis

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

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Protective role of IFN-γ in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production

Cited by 43 publications

References 64 publications

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Mutual antagonistic relationship between prostaglandin E2 and IFN‐γ: Implications for rheumatoid arthritis

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

Contact Info

Product

Resources

About

Mutual antagonistic relationship between prostaglandin E₂ and IFN‐γ: Implications for rheumatoid arthritis