Flavopiridol Protects Against Inflammation by Attenuating Leukocyte-Endothelial Interaction via Inhibition of Cyclin-Dependent Kinase 9

Abstract

Objective-The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death-inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte-endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms. Methods and Results-Flavopiridol suppressed concanavalin A-induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-␣-induced leukocyte-endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-B-dependent transcription. Flavopiridol did not affect inhibitor of B (IB) kinase, the degradation and phosphorylation of IB␣, nuclear translocation of p65, or nuclear factor-B (NF-B) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase C (PKC), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol. Conclusion-Our

CDK9-Dependent Transcriptional Elongation in the Innate Interferon-Stimulated Gene Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells

“…We previously provided evidence that CDK9 is important for the activation of a subset of rapidly inducible NF-B-dependent cytokine genes (69). This work was extended in studies examining the effect of blocking CDK9 activity and found decreased ICAM-1 expression in human endothelial cells and reduced leukocyte recruitment (72). Our present study further demonstrates that CDK9-initiated transcription elongation also plays a major role in the IRF3-induced ISG response.…”

Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

“…An increasing number of agents have been identified to interfere with the pathogenicity of atherosclerosis by targeting CDKS. Of these, CDK9 has been shown to exhibit marked characteristics in controlling inflammation (12). In a previous study (unpublished data), results of the 2-D proteomics analysis revealed that CDK9 was highly expressed in the serum of patients with atherosclerosis.…”

“…Additionally, it effectively limited murine hepatitis induced by concanavalin A (ConA), which triggers a strong and rapid leukocyte-dependent inflammatory liver injury (38). Roscovitine protected against acute graft-versus-host disease by blocking the clonal expansion of T cells (12) and against glomerulonephritis by inhibiting the proliferative response of T and B cells (39). Thus, the anti-inflammatory effect of CDKs inhibitors has been ascribed to its inhibition of the proliferation and induction of cell death in immune cells and.…”

“…The abovementioned findings show that the anti-inflammatory action of flavopiridol is associated with the reduction of leukocyte infiltration and cell adhesion molecule expression which emphasize the inhibition of CDK9 as an interesting approach against inflammation-associated pathologies. CDK9 inhibition is considered to have potential value in the combat against inflammation (12). Independent of its function as a subunit of P-TEFb, CDK9 is considered to interact with κB p65 and to repress NF-κ cytoplasmic regions of gp130, the receptor for the proinflammatory cytokine IL-6.…”

“…HEXIM1, an endogenous inhibitor of P-TEFb, is associated with NF-κB dependent gene transcription in smooth muscle cells. Authors of that study (12) assessed the action of CDK9 suppression on leukocyte-EC interaction and, in particular, on endothelial activation, an important inflammation-triggering event. Low-dose flavopiridol effectively protects against inflammation-induced interactions between leukocytes and the endothelium, primarily by blocking endothelial activation.…”