HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by François, S. Articles by Elbim, C. Search for Related Content PubMed PubMed Citation Articles by François, S. Articles by Elbim, C.

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-B Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

Stéphanie François^*,, Jamel El Benna^*, Pham M. C. Dang^*, Eric Pedruzzi^*, Marie-Anne Gougerot-Pocidalo^1,*, and Carole Elbim^*,

^* Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 479, Faculté Xavier Bichat, and Service d’Immunologie et d’Hématologie, Centre Hospitalo-Universitaire Xavier Bichat, Paris, France

Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood. LPS (TLR4), peptidoglycan (TLR2), R-848 (TLR7/8), and CpG-DNA (TLR9) were equally effective at delaying spontaneous apoptosis of PMN, while PamCSK4 (TLR1/2), macrophage-activating lipopeptide-2 (TLR2/6), flagellin (TLR5), and loxoribine (TLR7) were less effective or inactive. TLR agonists found to delay apoptosis also extended the functional life span of PMN. Analysis of signaling pathways revealed that the antiapoptotic effect of TLR agonists required NF-B and PI3K activation. Furthermore, analysis of intact cells by flow cytometry showed that TLR agonists delaying PMN apoptosis increased phosphorylation of Akt, a major target of PI3K. This effect was associated with a PI3K-dependent increase in heat shock protein 27 phosphorylation, which has been reported to play a key role in PMN survival. Finally, the TLR-induced delay in PMN apoptosis was associated with increased levels of Mcl-1 and A1, which are antiapoptotic members of the Bcl-2 family. These effects were reversed by PI3K and NF-B inhibitors, respectively. TLR activation also led to PI3K-dependent phosphorylation of the proapoptotic protein Bad. Taken together, our results strongly suggest a role of NF-B and PI3K in TLR-induced PMN survival, leading to modulation of Bcl-2 family molecules.

This article has been cited by other articles:

				L. Zheng, N. Asprodites, A. H. Keene, P. Rodriguez, K. D. Brown, and E. Davila TLR9 engagement on CD4 T lymphocytes represses {gamma}-radiation-induced apoptosis through activation of checkpoint kinase response elements Blood, March 1, 2008; 111(5): 2704 - 2713. [Abstract] [Full Text] [PDF]

				C. Beauvillain, Y. Delneste, M. Scotet, A. Peres, H. Gascan, P. Guermonprez, V. Barnaba, and P. Jeannin Neutrophils efficiently cross-prime naive T cells in vivo Blood, October 15, 2007; 110(8): 2965 - 2973. [Abstract] [Full Text] [PDF]

				C. Hoarau, B. Gerard, E. Lescanne, D. Henry, S. Francois, J.-J. Lacapere, J. El Benna, P. M.-C. Dang, B. Grandchamp, Y. Lebranchu, et al. TLR9 Activation Induces Normal Neutrophil Responses in a Child with IRAK-4 Deficiency: Involvement of the Direct PI3K Pathway J. Immunol., October 1, 2007; 179(7): 4754 - 4765. [Abstract] [Full Text] [PDF]

				M. Charmoy, R. Megnekou, C. Allenbach, C. Zweifel, C. Perez, K. Monnat, M. Breton, C. Ronet, P. Launois, and F. Tacchini-Cottier Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection J. Leukoc. Biol., August 1, 2007; 82(2): 288 - 299. [Abstract] [Full Text] [PDF]

				S. Jaillon, G. Peri, Y. Delneste, I. Fremaux, A. Doni, F. Moalli, C. Garlanda, L. Romani, H. Gascan, S. Bellocchio, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps J. Exp. Med., April 16, 2007; 204(4): 793 - 804. [Abstract] [Full Text] [PDF]

				I. Valera, A. G. Vigo, S. Alonso, L. Barbolla, M. S. Crespo, and N. Fernandez Peptidoglycan and mannose-based molecular patterns trigger the arachidonic acid cascade in human polymorphonuclear leukocytes J. Leukoc. Biol., April 1, 2007; 81(4): 925 - 933. [Abstract] [Full Text] [PDF]

				E. Lombardo, A. Alvarez-Barrientos, B. Maroto, L. Bosca, and U. G. Knaus TLR4-Mediated Survival of Macrophages Is MyD88 Dependent and Requires TNF-{alpha} Autocrine Signalling J. Immunol., March 15, 2007; 178(6): 3731 - 3739. [Abstract] [Full Text] [PDF]

				M. Wiens, M. Korzhev, S. Perovic-Ottstadt, B. Luthringer, D. Brandt, S. Klein, and W. E. G. Muller Toll-Like Receptors Are Part of the Innate Immune Defense System of Sponges (Demospongiae: Porifera) Mol. Biol. Evol., March 1, 2007; 24(3): 792 - 804. [Abstract] [Full Text] [PDF]

				I. Dzhagalov, A. St. John, and Y.-W. He The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages Blood, February 15, 2007; 109(4): 1620 - 1626. [Abstract] [Full Text] [PDF]

				P. Lewkowicz, N. Lewkowicz, A. Sasiak, and H. Tchorzewski Lipopolysaccharide-Activated CD4+CD25+ T Regulatory Cells Inhibit Neutrophil Function and Promote Their Apoptosis and Death J. Immunol., November 15, 2006; 177(10): 7155 - 7163. [Abstract] [Full Text] [PDF]

				M. Vijay-Kumar, H. Wu, R. Jones, G. Grant, B. Babbin, T. P. King, D. Kelly, A. T. Gewirtz, and A. S. Neish Flagellin Suppresses Epithelial Apoptosis and Limits Disease during Enteric Infection Am. J. Pathol., November 1, 2006; 169(5): 1686 - 1700. [Abstract] [Full Text] [PDF]

				X.-Q. Wang, K. Bdeir, S. Yarovoi, D. B. Cines, W. Fang, and E. Abraham Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury J. Immunol., October 15, 2006; 177(8): 5550 - 5557. [Abstract] [Full Text] [PDF]

				H. Wang, M. W. Nicholas, K. L. Conway, P. Sen, R. Diz, R. M. Tisch, and S. H. Clarke EBV Latent Membrane Protein 2A Induces Autoreactive B Cell Activation and TLR Hypersensitivity. J. Immunol., September 1, 2006; 177(5): 2793 - 2802. [Abstract] [Full Text] [PDF]

				C. A. Lindemans, P. J. Coffer, I. M. M. Schellens, P. M. A. de Graaff, J. L. L. Kimpen, and L. Koenderman Respiratory Syncytial Virus Inhibits Granulocyte Apoptosis through a Phosphatidylinositol 3-Kinase and NF-{kappa}B-Dependent Mechanism J. Immunol., May 1, 2006; 176(9): 5529 - 5537. [Abstract] [Full Text] [PDF]

				S. T. Qureshi, X. Zhang, E. Aberg, N. Bousette, A. Giaid, P. Shan, R. M. Medzhitov, and P. J. Lee Inducible Activation of TLR4 Confers Resistance to Hyperoxia-Induced Pulmonary Apoptosis. J. Immunol., April 15, 2006; 176(8): 4950 - 4958. [Abstract] [Full Text] [PDF]

				H. Lu, W. Ouyang, and C. Huang Inflammation, a Key Event in Cancer Development Mol. Cancer Res., April 1, 2006; 4(4): 221 - 233. [Abstract] [Full Text] [PDF]

				E. S. Henson, X. Hu, and S. B. Gibson Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression Clin. Cancer Res., February 1, 2006; 12(3): 845 - 853. [Abstract] [Full Text] [PDF]