ArticleAmerican journal of physiology. Cell physiology2009
Inhibition of CDKS by roscovitine suppressed LPS-induced *NO production through inhibiting NFkappaB activation and BH4 biosynthesis in macrophages.
Article in American journal of physiology. Cell physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 48 citations in OpenAlex.
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- The Role of CDKs in the Regulation of the Monocyte/Macrophage Immune Response.Current medicinal chemistry · 2026Review
- Impact of overexpression of wild-type CFTR and elexacaftor-tezacaftor-ivacaftor on oxylipin production by the CFBE41o- bronchial epithelial cell line.Prostaglandins & other lipid mediators · 2025Article
- ThemBio · 2025Article
- Inhibition of CDK5 signaling mediated inflammation in macrophages promotes cutaneous wound healing.Scientific reports · 2025Article
- Disruption of CDK5 regulatory subunit 1, p35, limits immunosuppressive M2 macrophages while maintaining functional M1 macrophages.Frontiers in immunology · 2025Article
- Evaluation of Anti-Neuroinflammatory Activity of Isatin Derivatives in Activated Microglia.Molecules (Basel, Switzerland) · 2023Article
- Epigenetic regulation of macrophage polarization in wound healing.Burns & trauma · 2023Review
- Article
- Inhibition of Cyclin-Dependent Kinase 9 Downregulates Cytokine Production Without Detrimentally Affecting Human Monocyte-Derived Macrophage Viability.Frontiers in cell and developmental biology · 2022Article
- In Vitro Replication Inhibitory Activity of Xanthorrhizol against Severe Acute Respiratory Syndrome Coronavirus 2.Biomedicines · 2021Article
- Review
- Cell Division Cycle 2 Protects Neonatal Rats Against Hyperoxia-Induced Bronchopulmonary Dysplasia.Yonsei medical journal · 2020Article
- Inhibition of Cyclin-dependent Kinase 2 Signaling Prevents Liver Ischemia and Reperfusion Injury.Transplantation · 2019Article
- Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation.Frontiers in immunology · 2019Article
- Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages.Oncotarget · 2018Review
- Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity.Journal of neuroinflammation · 2018Article
- Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.Journal of innate immunity · 2016Review
- Therapeutic targeting of replicative immortality.Seminars in cancer biology · 2015Review
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
In inflammatory diseases, tissue damage is critically associated with nitric oxide ((*)NO) and cytokines, which are overproduced in response to cellular release of endotoxins. Here we investigated the inhibitory effect of roscovitine, a selective inhibitor of cyclin-dependent kinases (CDKs) on (*)NO production in mouse macrophages. In RAW264.7 cells, we found that roscovitine abolished the production of (*)NO induced by lipopolysaccharide (LPS). Moreover, roscovitine significantly inhibited LPS-induced inducible nitric oxide synthase (iNOS) mRNA and protein expression. Our data also showed that roscovitine attenuated LPS-induced phosphorylation of IkappaB kinase beta (IKKbeta), IkappaB, and p65 but enhanced the phosphorylation of ERK, p38, and c-Jun NH(2)-terminal kinase (JNK). In addition, roscovitine dose dependently inhibited LPS-induced expression of cyclooxygenase-2 (COX)-2, IL-1beta, and IL-6 but not tumor necrosis factor (TNF)-alpha. Tetrahydrobiopterin (BH(4)), an essential cofactor for iNOS, is easily oxidized to 7,8-dihydrobiopterin (BH(2)). Roscovitine significantly inhibited LPS-induced BH(4) biosynthesis and decreased BH(4)-to-BH(2) ratio. Furthermore, roscovitine greatly reduced the upregulation of GTP cyclohydrolase-1 (GCH-1), the rate-limiting enzyme for BH(4) biosynthesis. Using other CDK inhibitors, we found that CDK1, CDK5, and CDK7, but not CDK2, significantly inhibited LPS-induced (*)NO production in macrophages. Similarly, in isolated peritoneal macrophages, roscovitine strongly inhibited (*)NO production, iNOS, and COX-2 upregulation, activation of NFkappaB, and induction of GCH-1 by LPS. Together, our data indicate that roscovitine abolishes LPS-induced (*)NO production in macrophages by suppressing nuclear factor-kappaB activation and BH(4) biosynthesis, which might be mediated by CDK1, CDK5, and CDK7. Our results also suggest that roscovitine may inhibit inflammation and that CDKs may play important roles in the mechanisms by which roscovitine attenuates inflammation.
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