TLR2- and nucleotide-binding oligomerization domain 2-dependent Krüppel-like factor 2 expression downregulates NF-kappa B-related gene expression

J Immunol. 2010 Jul 1;185(1):597-604. doi: 10.4049/jimmunol.0901798. Epub 2010 Jun 4.


The release of potent proinflammatory mediators is not only central for mounting an efficient host response, but also bears the risk for deleterious excessive tissue-damaging inflammation. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance between a robust inflammatory response to kill pneumococci and loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krüppel-like factor (KLF)2 counterregulates pneumococci- and pattern recognition receptor-related human lung cell activation. Pneumococci induced KLF2 expression in vitro and in a murine pneumonia model. Activation of TLR2- and nucleotide-binding oligomerization domain protein 2-related signaling induced KLF2 expression in a PI3K-dependent manner. Overexpression of KLF2 downregulated pneumococci-, TLR2-, and nucleotide-binding oligomerization domain protein 2-related NF-kappaB-dependent gene expression and IL-8 release, whereas small interfering RNA-based silencing of KLF2 provoked an enhanced inflammatory response. KLF2-dependent downregulation of NF-kappaB activity is partly reversible by overexpression of the histone acetylase p300/CREB-binding protein-associated factor. In conclusion, KLF2 may act as a counterregulatory transcription factor in pneumococci- and pattern recognition receptor-related proinflammatory activation of lung cells, thereby preventing lung hyperinflammation and subsequent organ failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Gene Expression Regulation / immunology*
  • Humans
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology*
  • Kruppel-Like Transcription Factors / biosynthesis*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / physiology*
  • Mice
  • Multiple Organ Failure / genetics
  • Multiple Organ Failure / immunology
  • Multiple Organ Failure / prevention & control
  • NF-kappa B p50 Subunit / antagonists & inhibitors*
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Nod2 Signaling Adaptor Protein / physiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Pneumonia, Pneumococcal / genetics
  • Pneumonia, Pneumococcal / immunology*
  • Pneumonia, Pneumococcal / prevention & control
  • Streptococcus pneumoniae / immunology
  • Toll-Like Receptor 2 / biosynthesis
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / physiology*


  • Inflammation Mediators
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • NF-kappa B p50 Subunit
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Nfkb1 protein, mouse