Distinct roles for the NF-κB1 (p50) and c-Rel transcription factors in inflammatory arthritis

Campbell, Ian K.; Gerondakis, Steve; O’Donnell, Kristy; Wicks, Ian P.

doi:10.1172/jci8298

Cited by 166 publications

(130 citation statements)

References 52 publications

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“…The predominant subunit expressed at the CPJ, which is the site of joint erosion in RA, was NF-B1. This finding is consistent with the observations in experimental studies which have suggested that the Rel/NF-B subunits may have different roles in the pathogenensis of RA (10). Thus, NF-B1, but not c-Rel, is essential for the induction of both local joint inflammation and destruction.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have demonstrated that Rel/ NF-B blockade may modulate inflammatory mechanisms in the synovium (32). The predominant expression of NF-B1 at tissue sites adjacent to the CPJ is consistent with the suggestion from experimental studies that specific Rel/NF-B subunits may play distinct pathophysiologic roles in chronic arthritis (10). Thus, our results support the rationale for specific therapeutic inhibition of NF-B1 in RA.…”

Section: Discussionsupporting

confidence: 91%

“…Activated Rel/NF-B subunits are abundantly expressed in RA synovial tissue and in experimental models of arthritis (5)(6)(7)(8)(9). In studies involving experimental arthritis, there is evidence to suggest that the Rel/NF-B subunits play distinct roles in the pathogenesis of inflammatory arthritis (10). Thus, in c-Rel-deficient mice, resistance to acute arthritis, but not to chronic destructive arthritis, was observed.…”

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confidence: 99%

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Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Benito

Murphy

et al. 2004

Arthritis & Rheumatism

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Objective. To compare the expression of the Rel/ NF-B subunits, NF-B1 (p50) and RelA (p65), in paired synovial tissue samples selected from sites adjacent to and remote from the cartilage-pannus junction (CPJ) in patients with inflammatory arthritis.Methods. Synovial tissue was selected at arthroscopy from sites adjacent to the CPJ and from the suprapatellar pouch of patients who were referred to an early arthritis clinic. Tissue samples from patients with osteoarthritis (OA) undergoing knee arthroplasty were also studied. Rel/NF-B subunit activation and expression were measured by electrophoretic mobility shift assay and supershift analyses and by immunohistochemistry.Results. Tissue samples were obtained from 10 patients with rheumatoid arthritis (RA), 7 with a seronegative arthropathy (SnA), and 6 with OA. Rel/NF-B was abundantly expressed in all samples. In both RA and SnA synovial tissue, the absolute number of NF-B1؉ cells at the CPJ was significantly higher than at non-CPJ sites (P ‫؍‬ 0.006 and P ‫؍‬ 0.02, respectively). The proportion of cells expressing NF-B1 was also significantly higher at the CPJ compared with non-CPJ sites (P ‫؍‬ 0.003 in RA, P ‫؍‬ 0.009 in SnA). The numbers of RelA؉ cells were consistently lower throughout. In RA synovial tissue, but not in SnA synovial tissue, both the absolute number and the proportion of RelA؉ cells were significantly higher at the CPJ than at non-CPJ sites (P ‫؍‬ 0.003 and P ‫؍‬ 0.01, respectively). In OA synovial tissue, the numbers of cells expressing NF-B1 and RelA were similar to those observed at the non-CPJ sites in all inflammatory tissues studied.Conclusion. In this study of early inflammatory arthritis, expression of NF-B1 in synovial tissue was highest at sites most likely to be associated with joint erosion. These observations are consistent with a critical role of NF-B1 in joint destruction, and support the rationale for specific therapeutic inhibition of NF-B in RA.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

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Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Benito

Murphy

et al. 2004

Arthritis & Rheumatism

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“…Previous studies have shown that NF-jB activation increases the expression levels of inflammatory molecules in FLS and protects cells against TNF-a and Fas ligand-induced apoptosis. In vivo suppression of NF-jB enhanced apoptosis in the synovium of rats with experimentallyinduced arthritis (Chen et al, 1999;Campbell et al, 2000). In the present study, we found that the p65 subunit of NF-jB was only weakly induced by rhEndostatin in contrast to c-jun mRNA and c-Jun protein.…”

Section: Discussionsupporting

confidence: 51%

“…##P < 0.01 vs. the AA control group. initiation and perpetuation of RA (Han et al, 1998;Sioud et al, 1998;Chen et al, 1999;Campbell et al, 2000). The main activated form of NF-jB is a heterodimer of the p65 subunit and either a p50 or p52 subunit, and immunohistochemical analyses demonstrated that p50 and p65 NF-jB proteins are present in the nuclei of cells in the synovial intimal lining.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Fibroblast‐Like Synoviocyte Apoptosis Induced by Recombinant Human Endostatin in Rats with Adjuvant Arthritis

Huang

Chen

et al. 2008

The Anatomical Record

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by pronounced synovial hyperplasia, in which there may be an imbalance between the growth and death of fibroblast-like synoviocytes (FLS). The present study was undertaken to examine the effect of recombinant human endostatin (rhEndostatin) on FLS apoptosis in experimental RA. Adjuvant arthritis (AA) was induced in male Sprague Dawley (SD) rats. Using cultured AA FLS obtained from these rats, the apoptosis process was measured by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) as well as Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) labeling methods. In addition, the expression levels of the Fas, c-jun, NFjB, and caspase-3 gene products in synovial tissues were quantified by quantitative real-time polymerase chain reaction (qPCR) and/or Western blotting assays. Our data revealed that rhEndostatin induced apoptosis in AA FLS. The number and signal density of TUNEL-positive cells were significantly increased in rats treated with rhEndostatin (2.5 mg/kg). The percentage of Annexin V-FITC-positive cells was 6.67% after treatment with rhEndostatin at 25 mg/mL for 48 hr, compared with only 3.32% among untreated control cells. There were significant increases in Fas mRNA, c-jun mRNA, c-Jun protein, and caspase-3 (p20) protein in AA synovial tissues treated with rhEndostatin (2.5 mg/kg), whereas no significant difference in NFjB expression was detected between treated and untreated tissues. These findings indicate that rhEndostatin has a therapeutic effect on RA by inducing FLS apoptosis, which is strongly associated with increased expression of Fas, c-jun, and caspase-3, but not NFjB.

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Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis

Lawlor¹,

Campbell²,

O’Donnell³

et al. 2001

Arthritis & Rheumatism

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Objective To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by methylated bovine serum albumin (mBSA) and interleukin‐1 (IL‐1). Methods Mice were injected intraarticularly with mBSA on day 0 and subcutaneously with recombinant human IL‐1β on days 0–2. At day 7, knee joints were removed and assessed histologically. Flow cytometry and RNase protection were used to analyze IL‐1–dependent events. Results C57BL/6 (B6), 129/Sv, and (B6 × 129/Sv)F1 hybrid mice, all H‐2b strains, were susceptible to mBSA/IL‐1–induced arthritis, whereas C3H/HeJ (H‐2k) mice were not. B6 mice lacking T and B cells (RAG‐1−/−) or major histocompatibility complex (MHC) class II antigens (MHCII−/−), and B6 mice treated with a CD4+ T cell–depleting monoclonal antibody, were resistant to disease. In contrast, B cell–deficient (μMT/μMT) mice developed arthritis at an incidence and severity similar to that of controls. RelB‐deficient (RelB−/−) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity. In B6 mice, flow cytometry demonstrated an IL‐1–dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA (mRNA) for the chemokines monocyte chemoattractant protein 1, macrophage inhibitory protein 2 (MIP‐2), RANTES, MIP‐1α, and MIP‐1β, in vivo and in vitro. Conclusion Arthritis induced by mBSA/IL‐1 is strain specific and dependent on CD4+ T lymphocytes and at least partially on RelB, but not on B lymphocytes or antibody. IL‐1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells. This model of acute monarticular arthritis is particularly suitable for further investigations into cell‐mediated immunity in arthritis and the role of IL‐1.

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Distinct roles for the NF-κB1 (p50) and c-Rel transcription factors in inflammatory arthritis

Cited by 166 publications

References 52 publications

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Mechanism of Fibroblast‐Like Synoviocyte Apoptosis Induced by Recombinant Human Endostatin in Rats with Adjuvant Arthritis

Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis

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