Early Activation of Pulmonary Nuclear Factor kappa B and Nuclear Factor Interleukin-6 in Polymicrobial Sepsis

101

109

Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of IκB in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-κB transcription factors. Despite this, endotoxin-inducible NF-κB-dependent innate immunity genes, like IL-1β, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that RelB, another member of the NF-κB family, is induced during the establishment of tolerance. RelB expression correlated with IL-1β repression, and sepsis patients showed increased RelB when compared with normal controls. Transient expression of RelB inhibited IL-1β in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased RelB expression in tolerant cells and restored endotoxin induction of IL-1β. When we examined tolerant cell extracts, we found transcriptionally inactive NF-κB p65/RelB heterodimers. Taken together, our findings demonstrate that RelB can repress proinflammatory gene expression, and suggest that RelB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.

Section: Regulation Of Relbsupporting

confidence: 71%

mentioning

confidence: 99%

Induction of RelB Participates in Endotoxin Tolerance

Yoza

Cousart

et al. 2006

101

109

“…We examined PI3K activity in the liver, lung, and heart because it is well established that these organs play a pivotal role in the response to septic injury, shock, and multiorgan failure (7,8,38). Although there were differences among the tissues, the overall trend was very similar, in that PI3K activity increased in response to sham surgery, glucan, or CLP.…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of the PI3K pathway in response to a clinically relevant model of sepsis and inflammation has not been studied. We investigated the effect of inhibiting PI3K activity in a murine model of polymicrobial sepsis (7)(8)(9). We focused on tissue PI3K activity, serum cytokine levels, splenocyte apoptosis, and survival outcome.…”

mentioning

confidence: 99%

Modulation of the Phosphoinositide 3-Kinase Pathway Alters Innate Resistance to Polymicrobial Sepsis

Williams¹,

Li²,

Ha³

et al. 2004

Self Cite

154

162

We examined the effect of modulating phosphoinositide 3-kinase (PI3K) activity in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Inhibition of PI3K activity with wortmannin increased serum cytokine levels and decreased survival time in septic mice. We have reported that an immunomodulator, glucan phosphate, induces protection in murine polymicrobial sepsis. We observed that glucan stimulated tissue PI3K activity, which positively correlated with increased survival in septic mice. We investigated the effect of PI3K inhibition on survival in septic mice treated with glucan. Treatment of mice with the PI3K inhibitors, wortmannin and LY294002, completely eliminated the protective effect of glucan, indicating that protection against septic mortality was mediated through PI3K. Inhibition of PI3K resulted in increased serum levels of IL1-β, IL-2, IL-6, IL-10, IL-12, and TNF-α in septic mice. Apoptosis is thought to play a central role in the response to septic injury. We observed that inhibition of PI3K activity in septic mice resulted in increased splenocyte apoptosis and a change in the anatomic distribution of splenocyte apoptosis. We conclude that PI3K is a compensatory mechanism that suppresses proinflammatory and apoptotic processes in response to sepsis and/or inflammatory injury. Thus, PI3K may play a pivotal role in the maintenance of homeostasis and the integrity of the immune response during sepsis. We also observed that glucan phosphate decreased septic morbidity and mortality through a PI3K-dependent mechanism. This suggests that stimulation of the PI3K pathway may be an effective approach for preventing or treating sepsis and/or septic shock.

“…4 In the lungs, many noxious/inflammatory stimuli have been shown to activate NF-B, implicating the NF-B pathway as a focal point for induction of lung inflammation. In vivo activators of NF-B in the lungs include intact bacteria, Gram-negative bacterial LPS, ozone, and silica delivered directly to the airways, as well as systemic inflammatory insults such as sepsis, hemorrhage, and direct liver injury (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). In rodent models of lung inflammation induced by LPS, pretreatment with relatively nonspecific inhibitors of NF-B activation has been found to diminish lung inflammation (11)(12)(13).…”

mentioning

confidence: 99%

Duration and Intensity of NF-κB Activity Determine the Severity of Endotoxin-Induced Acute Lung Injury

Everhart¹,

Han

Sherrill

et al. 2006

228

218

Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-κB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-κB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-κB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-κB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IκB kinase inhibitor (BMS-345541) to down-regulate NF-κB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-κB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-κB activation correlates with severity of lung injury, and interdiction in the NF-κB pathway is beneficial even after the onset of lung inflammation.