Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. ii. low levels of synovial fluid and synovial tissue interferon suggest that γgm‐interferon is not the primary macrophage activating factor

Firestein, Gary S.; Zvaifler, Nathan J.

doi:10.1002/art.1780300804

Cited by 161 publications

(84 citation statements)

References 29 publications

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“…The strongest activator of STAT-1 is IFN␥, although IL-6, IL-10, and IFN␣/␤ may also contribute to synovial STAT-1 activation (Table 1). It has been argued that synovial levels of IFN␥ in RA are too low to activate cells (2,23). However, the pattern of gene activation detected (10) is most consistent with a so-called "IFN␥ signature," and a recent study has identified a mechanism whereby concentrations of IFN␥ as low as 5 pg/ml (0.1 units/ml) activate robust expression of genes such as IP-10, a chemokine (18).…”

Section: Stat Activation In Ra Synovitismentioning

confidence: 75%

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

Ivashkiv

2003

Arthritis & Rheumatism

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Section: Stat Activation In Ra Synovitismentioning

confidence: 75%

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

Ivashkiv

2003

Arthritis & Rheumatism

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“…However, blockade of IFN-γ had only a minor effect on osteoclast formation in our assays, which is consistent with the poor capacity of IL-15 to stimulate IFN-γ release by NK cells (27). Notably, low levels of IFN-γ are present in the RA synovium (37), and clinical studies have failed to demonstrate that IFN-γ has an effect on bone resorption (38), suggesting that this cytokine plays a minor role in counterbalancing the effect of RANKL in vivo.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Söderström

Stein

Colmenero

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

150

153

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Osteoclasts are bone-eroding cells that develop from monocytic precursor cells in the presence of receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclasts are essential for physiological bone remodeling, but localized excessive osteoclast activity is responsible for the periarticular bone destruction that characteristically occurs in patients with rheumatoid arthritis (RA). The origin of osteoclasts at sites of bone erosion in RA is unknown. Natural killer (NK) cells, as well as monocytes, are abundant in the inflamed joints of patients with RA. We show here that such NK cells express both RANKL and M-CSF and are frequently associated with CD14 + monocytes in the RA synovium. Moreover, when synovial NK cells are cocultured with monocytes in vitro, they trigger their differentiation into osteoclasts, a process dependent on RANKL and M-CSF. As in RA, NK cells in the joints of mice with collagen-induced arthritis (CIA) express RANKL. Depletion of NK cells from mice before the induction of CIA reduces the severity of subsequent arthritis and almost completely prevents bone erosion. These results suggest that NK cells may play an important role in the destruction of bone associated with inflammatory arthritis.

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“…The protocol used for the isolation of rat synovial cells is a modified version of previously described methods (30). Briefly, the synovial membranes were isolated from the knees of healthy specific pathogen-free inbred Lewis female rats (Harlan Sprague-Dawley) under sterile conditions, and were digested in a phosphate-buffered saline (PBS) collagenase type IV (0.2 mg/ml) solution (Sigma) for 2 h in a humidified incubator containing 5% CO 2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

Charbonneau¹,

Harper²,

Grondin³

et al. 2007

Journal of Biological Chemistry

104

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Chronic hypoxia and inflammatory cytokines are hallmarks of inflammatory joint diseases like rheumatoid arthritis (RA), suggesting a link between this microenvironment and central pathological events. Because TACE/ADAM17 is the predominant protease catalyzing the release of tumor necrosis factor ␣ (TNF␣), a cytokine that triggers a cascade of events leading to RA, we examined the regulation of this metalloprotease in response to hypoxia and TNF␣ itself. We report that low oxygen concentrations and TNF␣ enhance TACE mRNA levels in synovial cells through direct binding of hypoxia-inducible factor-1 (HIF-1) to the 5 promoter region. This is associated with elevated TACE activity as shown by the increase in TNF␣ shedding rate. By the use of HIF-1-deficient cells and by obliterating NF-B activation, it was determined that the hypoxic TACE response is mediated by HIF-1 signaling, whereas the regulation by TNF␣ also requires NF-B activation. As a support for the in vivo relevance of the HIF-1 axis for TACE regulation, immunohistological analysis of TACE and HIF-1 expression in RA synovium indicates that TACE is up-regulated in both fibroblast-and macrophage-like synovial cells where it localizes with elevated expression of both HIF-1 and TNF␣. These findings suggest a mechanism by which TACE is increased in RA-affected joints. They also provide novel mechanistic clues on the influence of the hypoxic and inflammatory microenvironment on joint diseases.Tumor necrosis factor-␣ converting enzyme (TACE) 2 or ADAM17 was initially described as the predominant enzyme responsible for the physiological cleavage of membrane-anchored tumor necrosis factor-␣ (TNF␣), releasing it in soluble form (1, 2). This enzyme belongs to the ADAM (a disintegrin and metalloprotease domain) family of transmembrane, multidomain zinc metalloproteinases (3) and is expressed in a wide variety of cell types, including TNF␣ non-producing cells (1). Beside TNF␣, TACE was also shown to solubilize a wide variety of proteins including the receptors TNFR-I and TNFR-II (4), interleukin-1RII (5), interleukin-6R (6), and macrophage/colony-stimulating factor-R (7), the cytokine transforming growth factor-␣ (4), members of the membrane-bound epidermal growth factor family (4), the Notch receptor (8), the chemokine fractalkine (9), L-selectin (4), and the ␤-amyloid precursor protein (10). The importance of TACE substrates in a variety of physiological functions, including development, is underscored by the fact that in vivo inhibition of TACE or disruption of the TACE gene results in the death of mice between embryonic day 17.5 and the first day after birth, due to a number of developmental defects. In addition, the implication of TACE substrates in immunoregulation has made this enzyme an efficient therapeutic target in the treatment of a number of pathological conditions including airway inflammation, cancer, and arthritis.Because of the pathophysiological importance of TACE-mediated shedding, several studies have addressed the mechanism of TACE regulation. Sur...

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Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. ii. low levels of synovial fluid and synovial tissue interferon suggest that γgm‐interferon is not the primary macrophage activating factor

Cited by 161 publications

References 29 publications

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor α-induced Increases in Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Expression by Synovial Cells

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