Human neutrophils utilize a Rac/Cdc42-dependent MAPK pathway to direct intracellular granule mobilization toward ingested microbial pathogens

• Published in: Blood Vol. 101; no. 8; pp. 3240 - 3248
• Main Authors: Zhong, Bin, Jiang, Kun, Gilvary, Danielle L., Epling-Burnette, Pearlie K., Ritchey, Connie, Liu, Jinhong, Jackson, Rosalind J., Hong-Geller, Elizabeth, Wei, Sheng
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.2003; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Candida albicans; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - physiology; Cytoplasmic Granules - physiology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes, Dominant; Humans; Immunobiology; MAP Kinase Kinase 1; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - deficiency; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - physiology; Mitogen-Activated Protein Kinases - metabolism; Mutagenesis, Site-Directed; Myeloid cells: ontogeny, maturation, markers, receptors; Neutrophils - physiology; p21-Activated Kinases; Phagocytosis - physiology; Phosphorylation; Polynuclears; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - physiology; Recombinant Fusion Proteins - antagonists & inhibitors; Recombinant Fusion Proteins - physiology; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - physiology; Transduction, Genetic; Human; Extracellular signal-regulated protein kinase; Enzyme; Granulocyte; Mitogen-activated protein kinase; Natural immunity; Microorganism; Neutrophil; Defense; Phagocytosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2001-12-0180

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 ofCandida albicans.Contact withC albicanstriggered 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 onlyC 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 byC 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.