Inhibitor of nuclear factor ?B kinase ? is a key regulator of synovial inflammation

Tak, Paul P.; Gerlag, Daniëlle M.; Aupperle, Karl R.; Geest, Deliana A. Van De; Overbeek, Maria J.; Bennett, Brydon L.; Boyle, David L.; Manning, Anthony M.; Firestein, Gary S.

doi:10.1002/1529-0131(200108)44:8<1897::aid-art328>3.0.co;2-4

Cited by 232 publications

(135 citation statements)

References 36 publications

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“…62 Interestingly, injection of activated IKK2 induces the development of arthritis in rats, whereas intra-articular injection of a DN IKK2 in a rat adjuvant-induced arthritis is able to decrease the pathology. 63 In support of this, a selective IKK2 inhibitor, SC-514, has been shown to partially inhibit NF-kB in synovial fibroblasts. 64 One of the complications of chronic inflammatory diseases, such as inflammatory arthritis, is the loss of bone resulting from a massive influx and activation of osteoclasts at the site of inflammation.…”

Section: Nf-jb In Arthritismentioning

confidence: 85%

NF-κB and the regulation of hematopoiesis

2006

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Section: Nf-jb In Arthritismentioning

confidence: 85%

NF-κB and the regulation of hematopoiesis

2006

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“…R heumatoid arthritis (RA) 3 is an autoimmune disease characterized by infiltration of lymphocytes and macrophages, and hyperplasia of the synovial lining. In RA, synovial fibroblasts markedly increase in number, display a transformed phenotype, and invade and destroy adjacent cartilage (1).…”

Section: Il-6 and Matrix Metalloproteinase-1 Are Regulated By The Cycmentioning

confidence: 86%

“…In contrast, osteoarthritis (OA) synovial fibroblasts do not hyperproliferate or invade articular cartilage in vivo (2). Furthermore, RA synovial fibroblasts spontaneously secrete numerous cytokines and matrix metalloproteinases (MMP) including IL-6, IL-8, MMP-1, and MMP-3, which may be regulated by NF-B and/or AP-1 (3)(4)(5)(6)(7). In culture, IFN-␥ inhibits TNF-␣-induced RA synovial fibroblast cell cycle activity and MMP-1 production (8), and IL-4 suppresses proliferation and MMP-1 and 3 mRNA expression (9), suggesting that RA synovial fibroblast proliferation and secretion of proinflammatory mediators may be linked.…”

Section: Il-6 and Matrix Metalloproteinase-1 Are Regulated By The Cycmentioning

confidence: 88%

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Perlman

Bradley

Liu

et al. 2003

The Journal of Immunology

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During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 ± 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = −0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G0/G1 phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G0/G1 cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.

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“…AIA is initiated in Lewis rats by intradermal injection of CFA at the base of the tail (24,25). The genetic background of rats is important, in that both MHC and non-MHC genes contribute to their susceptibility to AIA (26).…”

Section: Evaluation Of Therapeutic Targets In Animal Models Of Arthritismentioning

confidence: 99%

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Bevaart¹,

Vervoordeldonk²,

Tak³

2010

Arthritis & Rheumatism

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There are accumulating data describing the association between diabetes and cancer mortality from Westernised populations. There are no data describing the relationship between diabetes and cancer mortality in African or South Asian populations from developing countries. We explored the relationship of abnormal glucose tolerance and diabetes on cancer mortality risk in a large, multi‐ethnic cohort from the developing nation of Mauritius. Population‐based surveys were undertaken in 1987, 1992 and 1998. The 9559 participants comprised 66% of South Asian (Indian), 27% of African (Creole), and 7% of Chinese descent. Cox's proportional hazards model with time varying covariates was used to obtain hazard ratios (HRs) and 95% confidence intervals (95% CI) for risk of cancer mortality, after adjustment for confounding factors. In men, but not women, cancer mortality risk increased with rising 2h‐PG levels with HR for the top versus bottom quintile of 2.77 (95%CI: 1.28 to 5.98). South Asian men with known diabetes had a significantly greater risk of cancer mortality than those with normal glucose tolerance (NGT) HR: 2.74 (95%CI: 1.00‐7.56). Overall, impaired glucose tolerance was associated with an elevated risk of cancer mortality compared to NGT (HR: 1.47, 95% CI: 0.98–2.19), though this was not significant. We have shown that the association between abnormal glucose tolerance and cancer extends to those of African and South Asian descent. These results highlight the importance of understanding this relationship in a global context to direct future health policy given the rapid increase in type 2 diabetes, especially in developing nations.

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Inhibitor of nuclear factor ?B kinase ? is a key regulator of synovial inflammation

Cited by 232 publications

References 36 publications

NF-κB and the regulation of hematopoiesis

NF-κB and the regulation of hematopoiesis

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

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