SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2001-12-0180. This Article Full Text Full Text (PDF) All Versions of this Article: 2001-12-0180v1 101/8/3240    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhong, B. Articles by Wei, S. Search for Related Content PubMed PubMed Citation Articles by Zhong, B. Articles by Wei, S. Related Collections Immunobiology Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2003, Vol. 101, No. 8, pp. 3240-3248 PHAGOCYTES Human neutrophils utilize a Rac/Cdc42-dependent MAPK pathway to direct intracellular granule mobilization toward ingested microbial pathogens Bin Zhong, Kun Jiang, Danielle L. Gilvary, Pearlie K. Epling-Burnette, Connie Ritchey, Jinhong Liu, Rosalind J. Jackson, Elizabeth Hong-Geller, and Sheng Wei From the Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Department of Interdisciplinary Oncology, Tampa; and Los Alamos National Laboratories, NM. Elevated levels of mitogen-activated protein kinase/extracellular regulatory kinase (MAPK/ERK) activity are frequently found in some cancer cells. In efforts to reduce tumor growth, attempts have been made to develop cancer therapeutic agents targeting the MAPK. Here, by use of biologic, biochemical, and gene manipulation methods in human polymorphonuclear neutrophils (PMNs), we have identified a key pathway important in normal cell function involving MAPK/ERK in PMNs for growth inhibition of Candida albicans. Contact with C albicans triggered MAPK/ERK activation in PMNs within 5 minutes, and blocking of MAPK/ERK activation, either by the pharmacologic reagent PD098059 or by dominant-negative MAPK kinase (MEK) expression via vaccinia viral delivery, suppressed antimicrobial activity. Rac and Cdc42, but not Ras or Rho, were responsible for this MAPK/ERK activation. Expression of dominant-negative Rac (N17Rac) or Cdc42 (N17Cdc42) eliminated not only C albicans- mediated ERK phosphorylation but also phagocytosis and granule migration toward the ingested microbes, whereas dominant-negative Ras (N17Ras) and Rho (N19Rho) did not. PAK1 (p21-activated kinase 1) activation is induced by C albicans, suggesting that PAK1 may also be involved in the Rac1 activation of MAPK/ERK. We conclude from these data that Rac/Cdc42-dependent activation of MAPK/ERK is a critical event in the immediate phagocytic response of PMNs to microbial challenge. Therefore, use of MAPK pharmacologic inhibitors for the treatment of cancer may result in the interruption of normal neutrophil function. A balance between therapeutic outcome and undesirable side effects must be attained to achieve successful and safe anticancer therapy. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. V. Shurin, I. L. Tourkova, G. S. Chatta, G. Schmidt, S. Wei, J. Y. Djeu, and M. R. Shurin Small Rho GTPases Regulate Antigen Presentation in Dendritic Cells J. Immunol., March 15, 2005; 174(6): 3394 - 3400. [Abstract] [Full Text] [PDF] M. B. Fessler, S. K. Young, S. Jeyaseelan, J. G. Lieber, P. G. Arndt, J. A. Nick, and G. S. Worthen A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 606 - 615. [Abstract] [Full Text] [PDF] C. Du, R. Calderone, J. Richert, and D. Li Deletion of the SSK1 Response Regulator Gene in Candida albicans Contributes to Enhanced Killing by Human Polymorphonuclear Neutrophils Infect. Immun., February 1, 2005; 73(2): 865 - 871. [Abstract] [Full Text] [PDF] G. M. Fuhler, G. J. Knol, A. L. Drayer, and E. Vellenga Impaired interleukin-8- and GRO{alpha}-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia J. Leukoc. Biol., February 1, 2005; 77(2): 257 - 266. [Abstract] [Full Text] [PDF] C. Mille, G. Janbon, F. Delplace, S. Ibata-Ombetta, C. Gaillardin, G. Strecker, T. Jouault, P.-A. Trinel, and D. Poulain Inactivation of CaMIT1 Inhibits Candida albicans Phospholipomannan {beta}-Mannosylation, Reduces Virulence, and Alters Cell Wall Protein {beta}-Mannosylation J. Biol. Chem., November 12, 2004; 279(46): 47952 - 47960. [Abstract] [Full Text] [PDF] S. E. Pontow, N. V. Heyden, S. Wei, and L. Ratner Actin Cytoskeletal Reorganizations and Coreceptor-Mediated Activation of Rac during Human Immunodeficiency Virus-Induced Cell Fusion J. Virol., July 1, 2004; 78(13): 7138 - 7147. [Abstract] [Full Text] [PDF] G. M. Fuhler, K. A. Cadwallader, G. J. Knol, E. R. Chilvers, A. L. Drayer, and E. Vellenga Disturbed granulocyte macrophage-colony stimulating factor priming of phosphatidylinositol 3,4,5-trisphosphate accumulation and Rac activation in fMLP-stimulated neutrophils from patients with myelodysplasia J. Leukoc. Biol., July 1, 2004; 76(1): 254 - 262. [Abstract] [Full Text] [PDF] E. Werner GTPases and reactive oxygen species: switches for killing and signaling J. Cell Sci., January 15, 2004; 117(2): 143 - 153. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020