TLR2- and nucleotide-binding oligomerization domain 2-dependent Krüppel-like factor 2 expression downregulates NF-kappa B-related gene expression.
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.
Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité University Medicine Berlin, Berlin, Germany.
Janine
J
Zahlten
Robert
R
Steinicke
Bastian
B
Opitz
Julia
J
Eitel
Philippe Dje
PD
N'guessan
Maya
M
Vinzing
Martin
M
Witzenrath
Bernd
B
Schmeck
Sven
S
Hammerschmidt
Norbert
N
Suttorp
Stefan
S
Hippenstiel
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D018836:Inflammation Mediators; D051741:Kruppel-Like Transcription Factors; D052002:NF-kappa B p50 Subunit; D053473:Nod2 Signaling Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D051195:Toll-Like Receptor 2; C498314:Klf2 protein, mouse; C495945:Nod2 protein, mouse; C493486:Tlr2 protein, mouse; C073701:Nfkb1 protein, mouse