GeneChip Analyses of Global Transcriptional Responses of Murine Macrophages to the Lethal Toxin of Bacillus anthracis

ABSTRACT We performed GeneChip analyses on RNA from Bacillus anthracis lethal toxin (LeTx)-treated RAW 264.7 murine macrophages to investigate global effects of anthrax toxin on host cell gene expression. Stringent analysis of data revealed that the expression of several mitogen-activated protein kinase kinase-regulatory genes was affected within 1.5 h post-exposure to LeTx. By 3.0 h, the expression of 103 genes was altered, including those involved in intracellular signaling, energy production, and protein metabolism.

[1]  R. Bhatnagar,et al.  Protein synthesis is required for expression of anthrax lethal toxin cytotoxicity , 1994, Infection and immunity.

[2]  C. Harding,et al.  The Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and FcγR1 on Human Macrophages through Toll-Like Receptor 2 , 2003, Infection and Immunity.

[3]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[4]  J. Schellekens,et al.  Plasminogen Activator Inhibitor 1: A New Prognostic Marker in Septic Shock , 1989, Thrombosis and Haemostasis.

[5]  Jiahuai Han,et al.  RGS16 Attenuates Gαq-dependent p38 Mitogen-activated Protein Kinase Activation by Platelet-activating Factor* , 1999, The Journal of Biological Chemistry.

[6]  M. Mock,et al.  Role of Toxin Functional Domains in Anthrax Pathogenesis , 2000, Infection and Immunity.

[7]  F. Re,et al.  Toll-like Receptor 2 (TLR2) and TLR4 Differentially Activate Human Dendritic Cells* , 2001, The Journal of Biological Chemistry.

[8]  S. Leppla,et al.  Proteasome Activity Is Required for Anthrax Lethal Toxin To Kill Macrophages , 1999, Infection and Immunity.

[9]  V. Nachmias Small actin-binding proteins: the β-thymosin family , 1993 .

[10]  P. Barton,et al.  Structural characterization of the human fast skeletal muscle troponin I gene (TNNI2). , 2000, Gene.

[11]  Small actin-binding proteins: the beta-thymosin family. , 1993, Current opinion in cell biology.

[12]  T. van der Poll,et al.  Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. , 1995, Clinical science.

[13]  M. Lotz,et al.  The nerve growth factor/tumor necrosis factor receptor family , 1996, Journal of leukocyte biology.

[14]  A. Hall,et al.  Microinjection of recombinant p21rho induces rapid changes in cell morphology , 1990, The Journal of cell biology.

[15]  Yusuke Nakamura,et al.  EGR2 induces apoptosis in various cancer cell lines by direct transactivation of BNIP3L and BAK , 2003, Oncogene.

[16]  J. Zhang,et al.  Activation of platelet phosphatidylinositide 3-kinase requires the small GTP-binding protein Rho. , 1993, The Journal of biological chemistry.

[17]  R. Scolyer,et al.  The significance of the Wnt pathway in the pathology of human cancers. , 2004, Pathology.

[18]  T. van der Poll,et al.  Bronchoalveolar coagulation and fibrinolysis in endotoxemia and pneumonia , 2003, Critical care medicine.

[19]  John A. Young,et al.  Identification of the cellular receptor for anthrax toxin , 2001, Nature.

[20]  R. Andreesen,et al.  Comparative analysis of CD137 and LPS effects on monocyte activation, survival, and proliferation. , 2000, Biochemical and biophysical research communications.

[21]  C. Bae,et al.  Determination of Interaction Sites on the Small G Protein RhoA for Phospholipase D* , 1998, The Journal of Biological Chemistry.

[22]  O. Yampolskaya,et al.  Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings , 2001, Modern Pathology.

[23]  Thomas F. Smith,et al.  Response of the Clinical Microbiology Laboratory to Emerging (New) and Reemerging Infectious Diseases , 2004, Journal of Clinical Microbiology.

[24]  M. Debenedette,et al.  4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy1 , 2001, The Journal of Immunology.

[25]  J. Regan,et al.  Phosphorylation of Glycogen Synthase Kinase-3 and Stimulation of T-cell Factor Signaling following Activation of EP2 and EP4 Prostanoid Receptors by Prostaglandin E2 * , 2002, The Journal of Biological Chemistry.

[26]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[27]  S. Akira,et al.  Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. , 1999, Immunity.

[28]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992 .

[29]  S. Leppla,et al.  Characterization of macrophage sensitivity and resistance to anthrax lethal toxin , 1993, Infection and immunity.

[30]  A. Ashworth,et al.  The Dual Specificity Phosphatases M3/6 and MKP-3 Are Highly Selective for Inactivation of Distinct Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.

[31]  S. Leppla,et al.  Internalization and processing of Bacillus anthracis lethal toxin by toxin-sensitive and -resistant cells. , 1989, The Journal of biological chemistry.

[32]  J. Sha,et al.  Identification of Aeromonas hydrophila Cytotoxic Enterotoxin-induced Genes in Macrophages Using Microarrays* , 2003, Journal of Biological Chemistry.

[33]  J. Regan,et al.  Prostaglandin E2 Induced Functional Expression of Early Growth Response Factor-1 by EP4, but Not EP2, Prostanoid Receptors via the Phosphatidylinositol 3-Kinase and Extracellular Signal-regulated Kinases* , 2003, The Journal of Biological Chemistry.

[34]  B. Bloom,et al.  Role of Macrophage Oxidative Burst in the Action of Anthrax Lethal Toxin , 1994, Molecular medicine.

[35]  M. Mock,et al.  Anthrax lethal factor cleaves the N‐terminus of MAPKKS and induces tyrosine/threonine phosphorylation of MAPKS in cultured macrophages , 1999, Journal of applied microbiology.

[36]  R. Andreesen,et al.  CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. , 1998, Journal of immunology.

[37]  K D Paull,et al.  Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. , 1998, Science.

[38]  M. Watarai,et al.  Effect of the lower molecular capsule released from the cell surface of Bacillus anthracis on the pathogenesis of anthrax. , 2002, The Journal of infectious diseases.

[39]  K. Druey,et al.  RGS16 inhibits signalling through the Gα13–Rho axis , 2003, Nature Cell Biology.

[40]  T. Martin,et al.  Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. , 1989, The Journal of clinical investigation.

[41]  P. Hanna,et al.  Biochemical and physiological changes induced by anthrax lethal toxin in J774 macrophage-like cells. , 1992, Molecular biology of the cell.

[42]  K. Kaibuchi,et al.  Phosphorylation of Adducin by Rho-Kinase Plays a Crucial Role in Cell Motility , 1999, The Journal of cell biology.

[43]  L. Jacobs,et al.  Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. , 2003, The Journal of infectious diseases.

[44]  Terry Farrah,et al.  The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death , 1994, Cell.

[45]  Tsonwin Hai,et al.  The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. , 2001, Gene.

[46]  P. Cohen,et al.  Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. , 1993, The Biochemical journal.

[47]  M. Lotz,et al.  A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family. , 1993, Gene.

[48]  K. Druey,et al.  RGS16 inhibits signalling through the G alpha 13-Rho axis. , 2003, Nature cell biology.

[49]  D. Acosta,et al.  On the role of macrophages in anthrax. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Mock,et al.  Lethal factor of Bacillus anthracis cleaves the N-terminus of MAPKKs: analysis of the intracellular consequences in macrophages. , 2000, International journal of medical microbiology : IJMM.

[51]  P. Godowski,et al.  Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. , 1999, Science.

[52]  H. Schwarz,et al.  Identification of CD137 as a potent monocyte survival factor , 1999, Journal of leukocyte biology.

[53]  M. Aepfelbacher,et al.  Yersinia V–Antigen Exploits Toll-like Receptor 2 and CD14 for Interleukin 10–mediated Immunosuppression , 2002, The Journal of experimental medicine.

[54]  Philip Cohen,et al.  GSK3 takes centre stage more than 20 years after its discovery. , 2001 .

[55]  H. Schwarz,et al.  CD137 induces proliferation and endomitosis in monocytes. , 1999, Blood.

[56]  J. Kienast,et al.  Increase of Plasminogen Activator Inhibitor Levels Predicts Outcome of Leukocytopenic Patients with Sepsis , 1996, Thrombosis and Haemostasis.

[57]  T. Schroer,et al.  Characterization of DLC-A and DLC-B, two families of cytoplasmic dynein light chain subunits. , 1994, Molecular biology of the cell.

[58]  A. Sher,et al.  Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2 1 , 2003, The Journal of Immunology.

[59]  Ken Dewar,et al.  Kif1C, a kinesin-like motor protein, mediates mouse macrophage resistance to anthrax lethal factor , 2001, Current Biology.

[60]  R. Jope,et al.  The glamour and gloom of glycogen synthase kinase-3. , 2004, Trends in biochemical sciences.

[61]  I. Dozmorov,et al.  Decreased glycogen synthase kinase 3‐beta levels and related physiological changes in Bacillus anthracis lethal toxin‐treated macrophages , 2003, Cellular microbiology.

[62]  Marc Prentki,et al.  Role for Activating Transcription Factor 3 in Stress-Induced β-Cell Apoptosis , 2004, Molecular and Cellular Biology.

[63]  A. Friedlander,et al.  Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. , 1986, The Journal of biological chemistry.

[64]  S. Bavari,et al.  Macrophage-Derived Cell Lines Do Not Express Proinflammatory Cytokines after Exposure to Bacillus anthracis Lethal Toxin , 2001, Infection and Immunity.

[65]  M. Mock,et al.  Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. , 2000, The Biochemical journal.

[66]  G. Bokoch,et al.  Physical association of the small GTPase Rho with a 68-kDa phosphatidylinositol 4-phosphate 5-kinase in Swiss 3T3 cells. , 1996, Molecular biology of the cell.

[67]  R. Treisman,et al.  The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF , 1995, Cell.

[68]  J. Rowley,et al.  Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure. , 1988, Proceedings of the National Academy of Sciences of the United States of America.