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Wang, Keqing; Hampson, Peter; Hazeldine, Jon; Krystof, Vladimir; Strnad, Miroslav; Pechan, Paul; Lord, Janet M.
Publisher: Public Library of Science (PLoS)
Journal: PLoS ONE
Languages: English
Types: Article
Subjects: Q, Hematology, R, Research Article, Biology, Genetics, Molecular Cell Biology, Science, Medicine, Immunity, Immunology
Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently, the broad range cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to increase neutrophil apoptosis, implicating CDKs in the regulation of neutrophil lifespan. To determine which CDKs were involved in regulating neutrophil lifespan we first examined CDK expression in human neutrophils and found that only three CDKs: CDK5, CDK7 and CDK9 were expressed in these cells. The use of CDK inhibitors with differing selectivity towards the various CDKs suggested that CDK9 activity regulates neutrophil lifespan. Furthermore CDK9 activity and the expression of its activating partner cyclin T1 both declined as neutrophils aged and entered apoptosis spontaneously. CDK9 is a component of the P-TEFb complex involved in transcriptional regulation and its inhibition will preferentially affect proteins with short half-lives. Treatment of neutrophils with flavopiridol, a potent CDK9 inhibitor, increased apoptosis and caused a rapid decline in the level of the anti-apoptotic protein Mcl-1, whilst Bcl2A was unaffected. We propose that CDK9 activity is a key regulator of neutrophil lifespan, preventing apoptosis by maintaining levels of short lived anti-apoptotic proteins such as Mcl-1. Furthermore, as inappropriate inhibition of neutrophil apoptosis contributes to chronic inflammatory diseases such as Rheumatoid Arthritis, CDK9 represents a novel therapeutic target in such diseases.
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    • 1. Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, et al. (2010) In vivo labeling with H20-H-2 reveals a human neutrophil lifespan of 5.4 days. Blood 116: 625-627.
    • 2. Brach MA, deVos S, Gruss HJ, Herrmann F (1992) Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colonystimulating factor is caused by inhibition of programmed cell death. Blood 80: 2920-2924.
    • 3. Raza K, Scheel-Toellner D, Lee CY, Pilling D, Curnow SJ, et al. (2006) Synovial fluid leukocyte apoptosis is inhibited in patients with very early rheumatoid arthritis. Arthritis Res Ther 8: R120.
    • 4. Leuenroth SJ, Grutkoski PS, Ayala A, Simms HH (2000) The loss of Mcl1 expression in human polymorphonuclear leukocytes promotes apoptosis. J Leukoc Biol 68: 158-166.
    • 5. Moulding DA, Quayle JA, Hart CA, Edwards SW (1998) Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. Blood 92: 2495-2502.
    • 6. Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, et al. (2006) Cyclindependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 12: 1056-1064.
    • 7. Klausen P, Bjerregaard MD, Borregaard N, Cowland JB (2004) End-stage differentiation of neutrophil granulocytes in vivo is accompanied by upregulation of p27kip1 and down-regulation of CDK2, CDK4 and CDK6. J Leukoc Biol 75: 569-578.
    • 8. Leitch AE, Riley NA, Sheldrake TA, Festa M, Fox S, et al. (2010) The cyclindependent kinase inhibitor R-roscovitine down regulates Mcl-1 to overcome pro-inflammatory survival signalling and drive neutrophil apoptosis. Eur J Immunol 40: 1127-1138.
    • 9. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, et al. (2000) Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 43: 2797-804.
    • 10. Johnson N, Bentley J, Wang L-Z, Newell DR, Robson CN, et al. (2010) Preclinical evaluation of cyclin-dependent kinase 1 and 2 inhibition in anti-estrogensensitive and resistant breast cancer cells. Br J Cancer 102: 342-350.
    • 11. Sroka IM, Heiss EH, Havlicek L, Totzke F, Aristei Y, et al. (2010) A novel roscovitine derivative potently induces G1-phase arrest in platelet-derived growth factor -BB activated vascular smooth muscle cells. Mol Pharmacol. 77: 255-261.
    • 12. Wang S, Fischer PM (2008) Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol Sci. 29: 302-313.
    • 13. Marshall NF, Peng J, Xie Z, Price DH (1996) Control of RNA polymerase II elongation potential by a novel carboxy-terminal domain kinase. J Biol Chem 271: 27176-27183.
    • 14. Gojo I, Zhang B, Fenston RG (2002) The cyclin dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res 8: 3527-3538.
    • 15. Rosato RR, Almenara JA, Kolla SS, Maggio SC, Coe S, et al. (2007) Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vironostat anti-leukaemic interactions. Mol Cancer Ther 6: 692-702.
    • 16. Nasreen N, Mohammed KA, Sanders KL, Hardwick J, Van Horn RD, et al. (2003) Pleural mesothelial cells modulate polymorphonuclear leukocyte apoptosis in empyema. J Clin Immunol 23: 1-10.
    • 17. Derouet M, Thomas L, Cross A, Moots RJ, Edwards SW (2004) Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1. J Biol Chem 279: 26915-26921.
    • 18. Scheel-Toellner D, Wang KQ, Henriquez NV, Webb PR, Craddock R, et al. (2002) Cytokine mediated inhibition of apoptosis in non-transformed T cells and neutrophils can be dissociated from PKB/AKT activation. Eur J Immunol 32: 486-493.
    • 19. Wang K, Scheel-Toellner D, Wong SH, Craddock R, Caamano J, et al. (2003) Inhibition of neutrophil apoptosis by type 1 interferon depends on cross-talk between PI-3-kinase, protein kinase C-d and NF-kB signaling pathways. J.Immunol. 171: 1035-1041.
    • 20. Rosales JL, Ernst JD, Hallows J, Lee KY (2004) GTP-dependent secretion from neutrophils is regulated by Cdk5. J Biol Chem. 279: 53932-53936.
    • 21. Garriga J, Bhattacharya S, Calbo J, Marshall RM, Truongcao M, et al. (2003) CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2. Mol Cell Biol. 23: 5165-5173.
    • 22. O'Keeffe B, Fong Y, Chen D, Zhou S, Zhou Q (2000) Requirement for a kinasespecific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated tat stimulation of HIV-1 transcription. J Biol Chem. 275: 279-287.
    • 23. Aldridge AJ (2002) Role of the neutrophil in septic shock and the adult respiratory distress syndrome. Eur J Surgery 168: 204-214.
    • 24. Wright HL, Moots RJ, Bucknall RC, Edwards SW (2010) Neutrophil function in inflammation and inflammatory diseases. Rheumatology 9: 1618-1631.
    • 25. Carvajal RD, Tse A, Shah MA, Lefkowitz RA, Gonen M, et al. (2009) A Phase II Study of Flavopiridol (Alvocidib) in Combination with Docetaxel in Refractory, Metastatic Pancreatic Cancer. Pancreatology 9: 404-409.
    • 26. Robak T, Jamroziak K, Robak P (2009) Current and Emerging Treatments for Chronic Lymphocytic Leukaemia. Drugs 69: 2415-2449.
    • 27. Sekine C, Sugihara T, Miyake S, Hirai H, Yoshida M, et al. (2008) Successful treatment of animal models of rheumatoid arthritis with small molecule cyclindependent kinase inhibitors. J Immunol 180: 1954-1961.
    • 28. Afford SC, Pongracz J, Stockley R, Crocker J, Burnett D (1992) The induction by human interleukin-6 of apoptosis in the promyelocytic cell line U937 and human neutrophils. J Biol Chem 267: 21612-21616.
    • 29. Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, et al. (1989) Macrophage phagocytosis of aging neutrophils in inflammation - Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 83: 865-875.
    • 30. Scheel-Toellner D, Wang K, Craddock R, Webb PR, McGettrick HM, et al. (2004) Reactive oxygen species limit neutrophil lifespan by activating death receptor signalling. Blood 104: 2557-2564.
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