Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators

Immunity. 2005 Sep;23(3):319-29. doi: 10.1016/j.immuni.2005.08.010.


Certain microbes evade host innate immunity by killing activated macrophages with the help of virulence factors that target prosurvival pathways. For instance, infection of macrophages with the TLR4-activating bacterium Bacillus anthracis triggers an apoptotic response due to inhibition of p38 MAP kinase activation by the bacterial-produced lethal toxin. Other pathogens induce macrophage apoptosis by preventing activation of NF-kappaB, which depends on IkappaB kinase beta (IKKbeta). To better understand how p38 and NF-kappaB maintain macrophage survival, we searched for target genes whose products prevent TLR4-induced apoptosis and a p38-dependent transcription factor required for their induction. Here we describe key roles for transcription factor CREB, a target for p38 signaling, and the plasminogen activator 2 (PAI-2) gene, a target for CREB, in maintenance of macrophage survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthrax / immunology
  • Apoptosis / genetics*
  • Apoptosis / immunology
  • Bacillus anthracis / immunology
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / immunology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Gene Expression Regulation / immunology*
  • In Situ Nick-End Labeling
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Plasminogen Activator Inhibitor 2 / genetics
  • Plasminogen Activator Inhibitor 2 / immunology
  • Plasminogen Activator Inhibitor 2 / metabolism
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Signal Transduction / immunology
  • Toll-Like Receptor 4
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • NF-kappa B
  • Plasminogen Activator Inhibitor 2
  • Receptors, Immunologic
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • p38 Mitogen-Activated Protein Kinases