TLR2- and Nucleotide-Binding Oligomerization Domain 2-Dependent Krüppel-Like Factor 2 Expression Downregulates NF-κB–Related Gene Expression

Zahlten, Janine; Steinicke, Robert; Opitz, Bastian; Eitel, Julia; N′Guessan, Philippe Dje; Vinzing, Maya; Witzenrath, Martin; Schmeck, Bernd; Hammerschmidt, Sven; Suttorp, Norbert; Hippenstiel, Stefan

doi:10.4049/jimmunol.0901798

Cited by 24 publications

(20 citation statements)

References 58 publications

(112 reference statements)

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“…In line with our results, PA infection of CF BECs increased KLF2 expression in an ExoSdependent manner 32 . Other bacterial species also enable to induce KLF2 expression 50,51 . Although the mechanism by which ExoS induces KLF2 expression is still unclear, our studies suggest that this induction is independent of RhoA, a potential target suggested by others 50 .…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

et al. 2014

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Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age-dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

et al. 2014

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“…Human primary small airway epithelial cells (SAECs) were obtained from Clonetics/Cambrex (Taufkirchen, Germany). Cells were cultured and infected as described previously [11]. Human DNA from BEAS-2B cells was prepared using the QIAampDNA Mini Kit (Qiagen, Hilden, Germany) following manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…S4f), indicating that viable pneumococci are required to trigger KLF4 expression in lung cells. Assuming that killed pneumococci are still recognised by TLR2 [11] and that bacteriuminduced TLR9-dependent signalling is reduced by heat inactivation [5], we tested TLR9 as a possible receptor for KLF4 induction.…”

Section: Klf4 Expression In Lung Cells Is Induced By Tlr9mentioning

confidence: 99%

TLR9- and Src-dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia

et al. 2012

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The release of potent pro-inflammatory mediators is crucial to mounting an efficient host response during infection. However, excessive inflammation may lead to deleterious tissue damage. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance between a robust inflammatory response necessary to kill pneumococci and the loss of organ function determines the outcome of the disease.We assessed the regulation of the potent anti-inflammatory cytokine interleukin (IL)-10 in pneumococcal infection via Western blot, ELISA and chromatin immunoprecipitation analysis.Streptococcus pneumoniae induced IL-10 expression in mouse lungs and human lung epithelial cells. Pneumococcal infection resulted in a strong induction of Krueppel-like factor (KLF)4 expression in vivo and in vitro. The induction of both IL-10 and KLF4 is mediated by a pathway involving bacterial DNA, Toll-like receptor (TLR)9, MyD88 and Src kinase. KLF4 is recruited to the il10 promoter, and small-interfering RNA-mediated knockdown of KLF4 expression blocked IL-10 expression during pneumococcal infection.In conclusion, KLF4 is induced in a bacterial DNA-TLR9-Src-dependent manner and regulates IL-10 expression, linking the detection of bacterial DNA by TLR9 to the control of an inflammatory response.

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“…31,32,49,50 NF-B has been reported to down-regulate TM expression indirectly by competing for the limited pool of p300 in the nucleus. 31,32,49,50 Acetylation has recently been demonstrated as a key mechanism for NF-B activation. 27,29,30 Our data showed that Sirt1 may act as a suppressor of NF-B acetylation/activation in the mouse lung after PM 2.5 exposure.…”

Section: Sirt1 Controls Lung Inflammation and Coagulation 2427mentioning

confidence: 99%

“…45,46 NF-B also physically interacts with p300, a transcriptional coactivator required for many transcription factors including those controlling TM expression. 31,32,49,50 NF-B has been reported to down-regulate TM expression indirectly by competing for the limited pool of p300 in the nucleus. 31,32,49,50 Acetylation has recently been demonstrated as a key mechanism for NF-B activation.…”

Section: Sirt1 Controls Lung Inflammation and Coagulation 2427mentioning

confidence: 99%

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Liu

Liang

et al. 2012

Blood

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Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-B acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. IntroductionExposure to ambient particulate matter (PM) air pollution has been associated with impaired pulmonary function and increased cardiovascular disease-related mortality including inflammation and thrombosis. 1-5 Acute exposure to increased ambient fine particulate matter Ͻ 2.5 m in diameter (PM 2.5 ) was estimated to cause the premature deaths of tens of thousands of people each year in the United States. 6 Urban particulate matter (UPM) PM 2.5, one of the major air pollutants closely monitored by the US Environmental Protection Agency (EPA), is a complex mixture of substances that are directly emitted into the air from dust, soot, smoke, and combustion. 6 To protect public health, the EPA issued the current 24-hour PM 2.5 standard at 35 g/m 3 . 6 Despite the enormous health problems caused by PM 2.5 exposure, there have been few studies performed to explore the molecular mechanisms of PM 2.5 -induced lung vascular dysfunction. PM 2.5 can reach deep in the lung to the small airway and alveoli, 6 and directly cause lung inflammation and injury. [7][8][9][10][11][12][13] The pulmonary complications may lead to detrimental effects on other organs, particularly cardiovascular dysfunction such as systemic microvascular dysfunction and thrombosis. 1,2,4,5,13 A recent study demonstrated that short-term UPM exposure triggered the activation of primary hemostasis in healthy mice, with no substantial secondary hemostasis activation, leading to arterial but not venous thrombosis. 5 Whereas another study showed that short-term UPM exposure may cause activation of coagulation responses and fibrin formation in the lung. 14 Tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) play important roles in coagulation and fibrinolysis cascades, respectively. TFPI is an inhibitor of tissue factor (TF)-mediated coagulation responses. 15 PAI-1, on the other hand, is a major regulator of fibrinolysis, which functions by in...

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TLR2- and Nucleotide-Binding Oligomerization Domain 2-Dependent Krüppel-Like Factor 2 Expression Downregulates NF-κB–Related Gene Expression

Cited by 24 publications

References 58 publications

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

TLR9- and Src-dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

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