Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

Park, Sung Dong; Cheon, So Yeong; Park, Tae Yoon; Shin, Bo Young; Oh, Hee-Kyun; Ghosh, Sankar; Koo, Bon‐Nyeo; Lee, Sang Kyou

doi:10.1016/j.bbrc.2015.07.008

Cited by 24 publications

(29 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the transcription of inflammatory cytokines was activated. And some reports indicated that NF- κ b pathway was activated during sepsis and increased expression of proinflammatory cytokines such as IL-6, IL-1 β , and TNF- α , leading to excessive inflammation response [23, 27]. In our present study, the activation of NF- κ b p65 in PBMC was markedly inhibited with maresin 1 treatment in CLP animals.…”

Section: Discussionsupporting

confidence: 59%

See 1 more Smart Citation

Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

Wang

et al. 2016

Mediators of Inflammation

View full text Add to dashboard Cite

Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS). Maresin 1 (Mar1) is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP) with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS) and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb) pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation.

show abstract

Section: Discussionsupporting

confidence: 59%

“…PBMC is one of main inflammatory mediators' sources during sepsis process. NF- κ b pathway is considered as a key regulator of inflammatory gene expression [23, 24]. It was reported that NF- κ B Inhibition mitigated lung injury induced by CLP [25].…”

Section: Discussionmentioning

confidence: 99%

Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

Wang

et al. 2016

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…These three transcription factors showed significant overlap in their transcriptional targets (Tables S1 and S3), suggesting that they may interact to orchestrate the effects of BDS on microglia. Though these transcription factors are known to play a critical role in mediating many immune functions including cell cycle progression, cytokine production, cell migration, phagocytosis, and cellular differentiation (Roy et al, 2006; Wen et al, 2010; Park et al, 2015), their role in guiding microglial function in the developing brain has not been studied. It will be of great interest to test whether a microglia-specific deletion of PU.1 or RelA during the second week of life is sufficient to recapitulate some of the developmental and behavioral changes seen in BDS mice.…”

Section: Discussionmentioning

confidence: 99%

Early life stress perturbs the maturation of microglia in the developing hippocampus

Delpech

Lan

Jin

et al. 2016

Brain, Behavior, and Immunity

149

152

View full text Add to dashboard Cite

Children exposed to abuse or neglect show abnormal hippocampal development and similar findings have been reported in rodent models. Using brief daily separation (BDS), a mouse model of early life stress, we previously showed that exposure to BDS impairs hippocampal function in adulthood and perturbs synaptic maturation, synaptic pruning, axonal growth and myelination in the developing hippocampus. Given that microglia are involved in these developmental processes, we tested whether BDS impairs microglial activity in the hippocampus of 14 (during BDS) and 28-day old mice (one week after BDS). We found that BDS increased the density and altered the morphology of microglia in the hippocampus of 14-day old pups, effects that were no longer present on postnatal day (PND) 28. Despite the normal cell number and morphology seen at PND28, the molecular signature of hippocampal microglia, assessed using the NanoString immune panel, was altered at both ages. We showed that during normal hippocampal development, microglia undergo significant changes between PND14 and PND28, including reduced cell density, decreased ex vivo phagocytic activity, and an increase in the expression of genes involved in inflammation and cell migration. However, microglia harvested from the hippocampus of 28-day old BDS mice showed an increase in phagocytic activity and reduced expression of genes that normally increase across development. Promoter analysis indicated that alteration in the transcriptional activity of PU.1, Creb1, Sp1, and RelA accounted for most of the transcriptional changes seen during normal microglia development and for most of the BDS-induced changes at PND14 and PND28. These findings are the first to demonstrate that early life stress dysregulates microglial function in the developing hippocampus and to identify key transcription factors that are likely to mediate these changes.

show abstract

“…The rapid activation of the NF‐κB pathway in sepsis has been reported widely ; upon activation, NF‐κB in turn activates rapidly the expression of a large number of genes, including PD‐L1 . Also, Takada et al .…”

Section: Discussionmentioning

confidence: 99%

Farnesyltransferase inhibitor FTI-277 inhibits PD-L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation

Liu

et al. 2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of programmed death 1 (PD-1) to programmed death ligand 1 (PD-L1) promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD-1/PD-L1 pathway plays an important role in chronic viral infection, bacterial infection and sepsis. However, the precise immunosuppressive and anti-inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by caecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment. However, the effect of inhibition of farnesyltransferase activity on overall survival rates in patients with sepsis and the specific signalling pathway involved remain to be investigated. In this study, mice with CLP-induced sepsis were treated with farnesyltransferase inhibitor (FTI-277), and PD-L1 expression on septic spleen lymphocytes was examined. Flow cytometric analysis revealed that PD-L1 is expressed constitutively on lymphocytes and that PD-L1 protein expression was up-regulated strongly following CLP. FTI-277 down-regulated PD-L1 mRNA and protein expression on septic spleen lymphocytes in a dose-dependent manner. This effect was associated closely with nuclear factor kappa B (NF-κB). In addition, the significant damping effect of FTI-277 on the PD-L1 signal promoted interferon (IFN)-γ secretion, interleukin (IL)-2 production and splenocyte proliferation in response to anti-CD3 CD28 antibodies in mice. Furthermore, FTI-277 reduced spleen lymphocyte apoptosis in septic mice. Therefore, FTI-277 regulates spleen lymphocyte activity via the PD-L1 signalling pathway, with significant anti-inflammatory effects attributable to suppression of the NF-κB pathway. Farnesyltransferase represents a valuable therapeutic target for the treatment of sepsis.

show abstract

Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

Cited by 24 publications

References 15 publications

Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

Early life stress perturbs the maturation of microglia in the developing hippocampus

Farnesyltransferase inhibitor FTI-277 inhibits PD-L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation

Contact Info

Product

Resources

About