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.