Role of nitric oxide in the activation of NF-κB, AP-1 and NOS II expression in articular chondrocytes

Mendes, Alexandrina Ferreira; Carvalho, AP; Mm, Caramona; Lopes, María Celeste

doi:10.1007/pl00000317

Cited by 52 publications

(58 citation statements)

References 36 publications

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“…Nonetheless, upregulated iNOS mRNA levels were detected upon culture in high glucose for 24 h, whereas measurable amounts of the protein and NO were detected after 72 h and required culture periods longer than, at least, 48 h. Moreover, NF-κB activation was maximal after exposure to high glucose for 1 h, while by 2 h the effect had returned to levels found in control cells cultured in regular medium (10 mM glucose) for the same period and remained as such for, at least, 24 h (1440 min). This kinetics of NF-κB activation is similar to that observed with other stimuli, like IL-1β, which allows iNOS protein to be detected much earlier [22] than observed here with high glucose. This suggests that other mechanisms required to induce iNOS expression and protein synthesis are delayed in response to high glucose when compared to IL-1β.…”

Section: Discussionsupporting

confidence: 87%

“…Once IκBs, in particular IκB-α, are degraded, NF-κB translocates to the nucleus promoting the transcription of its target genes. Therefore, activation of this transcription factor leads to its nuclear translocation that can be detected as the nuclear accumulation of p65 (Rel A), a major component of NF-κB dimers found in chondrocytes [22].…”

Section: High-glucose Induces Nf-κb P65 Translocation To the Nucleusmentioning

confidence: 99%

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Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

Rufino

Ribeiro

Ferreira

et al. 2017

JFMK

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To elucidate the mechanisms by which type 2 Diabetes Mellitus (DM2) constitutes a risk factor for the development and progression of osteoarthritis (OA), this work determined whether high glucose and/or high insulin, the hallmarks of DM2, are capable of activating the transcription factor, Nuclear Factor-κB (NF-κB), which plays a critical role in OA by inducing the expression of pro-inflammatory and catabolic genes. For this, we analyzed NF-κB activation by measuring the nuclear levels of p65 by western blot. As readouts of NF-κB activity, Interleukin-1β, Tumor Necrosis Factor-α, and inducible nitric oxide synthase (iNOS) expression were analyzed by real time RT-PCR and western blot. Culture of the human chondrocytic cell line, C28-I2, in high glucose (30 mM) increased nuclear NF-κB p65 levels in a time-dependent manner, relative to cells cultured in medium containing 10 mM glucose (regular culture medium). High glucose-induced NF-κB activation was inhibited by co-treatment with its specific inhibitor, Bay 11-7082, 5 µM. Culture of primary human chondrocytes under high glucose for 24 h increased IL-1β and TNF-α mRNA levels by 97% (p = 0.0066) and 85% (p = 0.0045), respectively, while iNOS mRNA and protein levels and NO production increased by 61% (p = 0.0017), 148% (p = 0.0089), and 70% (p = 0.049), respectively, relative to chondrocytes maintained in 10 mM glucose. Treatment of chondrocytic cells with 100 nM insulin was also sufficient to increase nuclear NF-κB p65 levels, independently of the glucose concentration in the culture medium. This study shows that hyperglycemia and hyperinsulinemia are independently sufficient to induce inflammatory responses in human chondrocytes, namely by activating NF-κB. This can be a relevant mechanism by which DM type 2 and other conditions associated with impaired glucose and insulin homeostasis, like obesity and the metabolic syndrome, contribute to the development and progression of OA.

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Section: Discussionsupporting

confidence: 87%

Section: High-glucose Induces Nf-κb P65 Translocation To the Nucleusmentioning

confidence: 99%

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

Rufino

Ribeiro

Ferreira

et al. 2017

JFMK

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“…The prolonged activated MAPK is proposed in turn to induce AP-1. NO has also been found to induce AP-1 in other cell systems (Mendes et al, 2002;Ishii et al, 2003) and AP-1 induction is associated with apoptosis and growth inhibition in other culture conditions (Fan et al, 2001;Taimor et al, 2001). Diazeniumdiolate compounds of this type thus represent a novel approach to growth regulation based upon prolonged alteration of MAPK signaling pathways.…”

Section: Discussionmentioning

confidence: 96%

JS‐K, a novel non‐ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c‐Jun phosphorylation via multiple MAP kinase pathways

Ren

Kar

Wang

et al. 2003

Journal Cellular Physiology

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JS-K, a non-ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen-activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c-Jun and AP-1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS-K. In addition to the well-described actions of JNK as a kinase for c-Jun, we show that c-Jun is also an ERK target. Furthermore, JS-K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS-K. These results suggest two possible mechanisms for the mediation of JS-K growth inhibitory actions, namely NO-induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS-K action is important in mediating its growth-inhibitory actions. JS-K thus represents a promising platform for novel growth inhibitory analog synthesis.

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“…NO release in chondrocytes which had been cultured in agarose gel for up to two weeks [29]. However, we did not examine p38 MAPK activity and expression of iNOS, which has previously been shown to be activated in response to IL1b in chondrocyte cultures [29][30]. Nevertheless, in most cases, the inhibitors could not restore cell proliferation and downregulated proteoglycan synthesis in the presence of the cytokine.…”

Section: Discussionmentioning

confidence: 99%

“…IL-1b has also been demonstrated to activate the p38 MAPK, iNOS and . NO pathway in cartilage explants and chondrocyte cultures [29][30]. The opposite effect was found for chondrocytes cultured in agarose constructs, such that the application of dynamic compression (15 %, 1 Hz frequency) counteracts the IL-1b induced release of .…”

Section: Introductionmentioning

confidence: 99%

Signal transduction pathways involving p38 MAPK, JNK, NFκB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1β and dynamic compression

et al. 2008

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The MAPK, AP-1 and NF-kappaB signalling pathways are involved in the upregulation of NO and PGE2 release by IL-1beta. Dynamic compression stimulates cell proliferation and proteoglycan synthesis in the presence of IL-1beta and/or inhibitors of the MAPKs and NFkappaB and AP-1 signalling pathways. This experimental approach could provide valuable information for the biophysical/pharmacological treatment of OA.

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Role of nitric oxide in the activation of NF-κB, AP-1 and NOS II expression in articular chondrocytes

Abstract: These results suggest that, in chondrocytes, NO is a key regulator of the signaling pathways leading from IL-I to NF-kappaB and AP-1 activation and to the expression of genes that are involved in the pathophysiology of arthritic diseases.

Cited by 52 publications

References 36 publications

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

JS‐K, a novel non‐ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c‐Jun phosphorylation via multiple MAP kinase pathways

Signal transduction pathways involving p38 MAPK, JNK, NFκB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1β and dynamic compression

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