A Selective IKK-2 Inhibitor Blocks NF-κB-dependent Gene Expression in Interleukin-1β-stimulated Synovial Fibroblasts

Kishore, Nandini; Sommers, Cindy; Mathialagan, Sumathy; Guzova, Julia A.; Yao, Min; Hauser, Scott D.; Huynh, Khai; Bonar, Sheri L.; Mielke, Cindy; Albee, Lee D.; Weier, Richard M.; Graneto, Matthew J.; Hanau, Cathleen; Perry, Thao; Tripp, Catherine S.

doi:10.1074/jbc.m211439200

Cited by 274 publications

(279 citation statements)

References 51 publications

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“…A requirement for NF-κB is shown using two different selective inhibitors, one that blocks IkB kinase (IKK) (SC) and the dissociation of IκB and NF-κB and one that directly inhibits NF-κB (JSH) (17,18). Moreover, the results show that the antineurogenic effects of acute stress result from inhibition of NSC proliferation (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…Activation of the hypothalamic-pituitary-adrenal axis and elevation of glucocorticoids are typically associated with antiinflammatory responses, including inhibition of NF-κB signaling, via inhibition of IKK and inhibition of NF-κB transcription (17,18). However, there are also reports that stress can increase the effects of NF-κB, including enhancement of inflammatory responses (13,14,27).…”

Section: Discussionmentioning

confidence: 97%

“…1A). Two selective structurally different NF-κB inhibitors were tested: JSH-23 (JSH) and SC-514 (SC) (17,18). Immediately after immobilization, rats were administered BrdU, a thymidine analogue that is incorporated into dividing cells (2 h post-BrdU injection).…”

Section: Nf-κb Signaling Mediates the Suppression Of Hippocampalmentioning

confidence: 99%

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Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Koo

Russo

Ferguson

et al. 2010

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

540

389

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Proinflammatory cytokines, such as IL-1β, have been implicated in the cellular and behavioral effects of stress and in mood disorders, although the downstream signaling pathways underlying these effects have not been determined. In the present study, we demonstrate a critical role for NF-κB signaling in the actions of IL-1β and stress. Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.M ood disorders represent a major health concern, affecting over 15% of the population in developed countries, resulting in enormous personal and economic costs and, in many cases, suicide (1, 2). Despite significant efforts, the neurobiological mechanisms underlying depression have not been characterized. Both genetic and environmental factors contribute to depression, and traumatic or repeated stress is known to precipitate or exacerbate mood disorders (3-5). In addition, proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, that are induced by injury and infection as well as by psychological stress have been implicated in depressive behavior in rodent models and depressed patients (6-8).Exposure to stress and depression can result in atrophy of limbic brain regions that control emotion and mood, including inhibition of neurogenesis in the adult hippocampus (5, 9, 10). Inhibition of neurogenesis is observed with many different types of physical and psychological stressors, but the types of cells, neural stem-like cells (NSCs) or intermediate transient amplifying neural progenitor cells (ANPs), that are influenced have not been characterized (9, 11). A role for proinflammatory cytokines is supported by a recent report that IL-1β signaling is necessary and sufficient for the antineurogenic and behavioral effects of stress (6). One possible signaling cascade that could mediate the effects of IL-1β is NF-κB, which is activated by IL-1β and other cytokines both in peripheral immune cells and in the brain (8,12). Chronic stress enhances the activation of NF-κB in response to inflammatory stimuli (13,14), and social stress increases NF-κB signaling in healthy subjects and produces an exaggerated response in depressed patients (15,16).In the present study, we investigate the role of NF-κB in the cellular and behavioral responses to acute and chronic stress. The results demonstrate that the inhibition of neurogenesis by stress occurs via activation of NF-κB in NSCs and that stress-induced anhedonia, a core symptom of depr...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

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Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Koo

Russo

Ferguson

et al. 2010

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

540

389

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“…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. The first proof that blocking NF-kB could potentially be therapeutically efficacious was obtained after the administration of a DN IkB in a mouse model of inflammatory arthritis.…”

Section: Nf-jb In Arthritismentioning

confidence: 99%

NF-κB and the regulation of hematopoiesis

2006

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“…To confirm that the different activity of NF-kB is the determinant for the different susceptibility to apoptosis, we stimulated preadipocytes with TNF-a in the absence or presence of SC-514, a selective inhibitor of IkB kinase-2/NF-kB, 21 and performed microscopic analyses. Like adipocytes, TNF-atreated preadipocytes showed dramatic cell damage only under the suppression of NF-kB (Figure 3b, left).…”

Section: Resultsmentioning

confidence: 99%

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Tamai

Shimada

Hiramatsu

et al. 2010

Laboratory Investigation

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Tumor necrosis factor-a (TNF-a) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-a caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-a selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-a, rapid activation of nuclear factor-kB (NF-kB) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-kB rendered preadipocytes susceptible to TNF-a-induced apoptosis, suggesting that different activity of NF-kB is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-g (PPARg) were upregulated. Treatment of preadipocytes with a PPARg agonist attenuated NF-kB activation and rendered the cells vulnerable to TNF-a-induced apoptosis. Conversely, treatment of adipocytes with a PPARg antagonist enhanced NF-kB activation and conferred resistance to TNF-a-induced apoptosis, suggesting involvement of PPARg in the suppression of NF-kB in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/ enhancer binding protein (C/EBP), especially C/EBPa and C/EBPb, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-kB in preadipocytes. Furthermore, transfection with siRNA for C/EBPa or C/EBPb enhanced activity of NF-kB in adipocytes, suggesting that C/EBP is also involved in the repression of NF-kB in adipocytes. These results suggested novel mechanisms by which TNF-a selectively deletes adipocytes in the adipose tissue. The C/EBP-and PPARg-mediated suppression of NF-kB may contribute to TNF-a-related loss of adipose tissue mass under certain pathological situations, such as cachexia.

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A Selective IKK-2 Inhibitor Blocks NF-κB-dependent Gene Expression in Interleukin-1β-stimulated Synovial Fibroblasts

Cited by 274 publications

References 51 publications

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

NF-κB and the regulation of hematopoiesis

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

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