Inhibition of cyclin‐dependent kinases by olomoucine and roscovitine reduces lipopolysaccharide‐induced inflammatory responses via down‐regulation of nuclear factor κB

Rs, Jhou; Kh, Sun; Gh, Sun; Hh, Wang; Chang, Chung-I; Hc, Huang; Sy, Lu; Sj, Tang

doi:10.1111/j.1365-2184.2009.00584.x

Cited by 30 publications

(27 citation statements)

References 36 publications

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“…Consistent with these findings, we have reported that flavopiridol, a pan-selective CDK inhibitor, potently inhibits NF-B-dependent gene expression (33). Additionally, murine 264.7 macrophages treated with olomoucine and roscovitine, selective inhibitors of CDK1, -2, -5, and -7, exhibit a reduction in lipopolysaccharide-induced inflammatory responses by down-regulating NF-B-dependent gene expression (42). Taken together, these studies suggest that CDKs regulate NF-B-dependent gene expression by various mechanisms and at multiple steps in the transcriptional activation process.…”

Section: Discussionsupporting

confidence: 47%

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

Choudhary

Rosenblatt

Fang

et al. 2011

Journal of Biological Chemistry

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Nuclear factor-B (NF-B) is an inducible cytoplasmic transcription factor that plays a role as a master regulator of airway mucosal inflammation. The prototypical ("canonical") NF-B pathway controls cytoplasmic to nuclear translocation in response to stimulation by the mononuclear cytokine, TNF. Despite intensive investigation, the spectrum of kinases involved in the canonical NF-B pathway has not yet been systematically determined. Here we have applied a high throughput siRNA-mediated loss-of-function screening assay to identify novel kinases important in TNF-induced NF-B signaling. Type II A549 epithelial cells stably expressing an IL-8/luciferase reporter gene optimized for high throughput siRNA format (Z score of 0.65) and siRNAs for 636 human kinases were reversetransfected and screened in the assay. 36 candidate genes were identified that inhibited TNF signaling with a Z score deviation of <؊1.3 in replicate plates. From this group, 11 kinases were selected for independent validation, of which eight were successfully silenced. Six kinases were validated, including ATM, CDK2, -5, and -7, CALM3, MAPAKP5, and MAP3K/MEKK3. The surprising function of ATM in TNF signaling was confirmed where reduced NF-B/RelA translocation and Ser-276 phosphorylation were seen in ATM ؊/؊ mouse embryo fibroblasts. These data indicate that ATM is a key regulatory kinase that may control global NF-B activation in the TNF-induced canonical pathway.Eukaryotic tissues respond to signals in their extracellular environment through the induction of long term phenotypic plasticity. An important mechanism for this plasticity is through the activation of cell surface receptors coupled to intracellular signal transduction networks, the activation of which, in turn, induces a reactive gene expression. One specific example occurs in airway mucosal surfaces that normally promote gas exchange, facilitate particulate matter clearance through the muco-ciliary escalator, and protect against oxidative damage (1). Within this surface, sentinel epithelial cells are responsible for activating the innate inflammatory response upon stimulation with macrophage-derived cytokines via the plasma membrane-anchored TNF/death receptor (TNFR) 2 superfamily (2, 3). Liganded TNFRs signal intracellularly through nuclear factor-B (NF-B), an inducible cytoplasmic transcription factor that temporally coordinates expression of gene networks, including interferon, cytokine, and anti-apoptotic genes (4 -6). As a result, the mucosal surface assumes a pathogen-resistant and proinflammatory phenotype. Because of its central role in airway inflammatory disease, the NF-B signaling pathway has been extensively investigated.Under resting conditions, NF-B is inhibited in the cytoplasm by binding to members of the IB family of inhibitory proteins, resulting in cytoplasmic retention and inactivation of its latent DNA binding activity. TNFR-ligand binding results in submembranous recruitment of death domains containing adapter molecules, including the TNF receptor-associated factors...

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Section: Discussionsupporting

confidence: 47%

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

Choudhary

Rosenblatt

Fang

et al. 2011

Journal of Biological Chemistry

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“…R-roscovitine was shown to reduce TNF-α, IL-6 and IL-1β mRNA levels in the RAW 264.7 cell line (19). We expanded these findings with protein measurements of TNF-α and KC in three mouse cell lines relevant for lung inflammatory responses.…”

Section: Discussionmentioning

confidence: 98%

“…Previously, R-roscovitine was shown to reduce COX-2, IL-6, IL-1β and TNF-α mRNA expression levels in LPSstimulated RAW264.7 cells (murine macrophages) (19,28). We set out to investigate the effect of R-roscovitine on protein levels, rather than mRNA expression levels, of inflammatory mediators.…”

Section: R-roscovitine Inhibits Lta-induced Inflammatory Mediator Promentioning

confidence: 99%

“…R-roscovitine's apoptosisinducing potential in PMNs has previously been established in several in vivo models of inflammation and infection, resulting in improved resolution of inflammation (20)(21)(22). Besides inducing beneficial PMN apoptosis, R-roscovitine possibly has direct antiinflammatory properties by inhibiting the transcription of proinflammatory cytokines in macrophages (19).…”

Section: Introductionmentioning

confidence: 99%

“…The purine analog R-roscovitine is a potent inhibitor of the cyclin-dependent kinase (CDK)-1, -2, -5 and -7, which have the ability to inhibit the cell cycle and to induce apoptosis, especially in PMNs (10,(17)(18)(19). R-roscovitine's apoptosisinducing potential in PMNs has previously been established in several in vivo models of inflammation and infection, resulting in improved resolution of inflammation (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

Hoogendijk

Roelofs

Duitman

et al. 2012

Mol Med

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Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/ MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.

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Post-ischemic scars and ‘The micro-metabolic-glia-cerebral changes”: do we know everything?

Savaliya,

Chavda,

Patel

et al. 2024

Neurosurg Rev

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Inhibition of cyclin‐dependent kinases by olomoucine and roscovitine reduces lipopolysaccharide‐induced inflammatory responses via down‐regulation of nuclear factor κB

Abstract: The findings of this study suggest that inhibition of cell-cycle progression is capable of reducing pro-inflammatory responses via down-regulation of NF-kappaB.

Cited by 30 publications

References 36 publications

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-κB (NF-κB) Activation Pathway

R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

Post-ischemic scars and ‘The micro-metabolic-glia-cerebral changes”: do we know everything?

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