Intestinal NF-κB is activated, mainly as p50 homodimers, by platelet-activating factor

Plaen, Isabelle G. De; Tan, Xiaodi; Chang, Hak; Qu, Xiao-Wu; Liu, Qian-Ping; Hsueh, Wei

doi:10.1016/s0005-2760(98)00024-1

Cited by 47 publications

(80 citation statements)

References 29 publications

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“…31 Necrotizing enterocolitis might be caused by the lack of tolerance to commensal bacteria during the colonization process, and IBD is thought to be caused by an inappropriate response of the host to its own resident luminal bacteria. 29 In a rat model of PAF-induced bowel injury, we have found that: (a) neutrophil influx into the intestine is increased and blocking neutrophil influx by blocking neutrophil-endothelial adhesion prevents neutrophil adhesion and subsequent bowel injury; 10 (b) intestinal NF-jB is activated 3 and the activated NF-jB is mostly immunolocalized to the epithelial cells of the villi and to some inflammatory cells of the lamina propria; 3 and (c) CXCL2, a major chemokine for neutrophils, is induced and mediates PAFinduced bowel injury and intestinal neutrophil recruitment. 12 A previous investigation 32 and our own study (data not shown) have found that LPS induces CXCL2 in the intestine in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

Plaen¹,

Han²,

Liu³

et al. 2006

Immunology

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SummaryCXCL2 (macrophage inflammatory protein-2 (MIP-2)), a critical chemokine for neutrophils, has been shown to be produced in the rat intestine in response to platelet-activating factor (PAF) and to mediate intestinal inflammation and injury. The intestinal epithelium, constantly exposed to bacterial products, is the first line of defence against micro-organisms. It has been reported that enterocytes produce proinflammatory mediators, including tumour necrosis factor (TNF) and PAF, and we showed that lipopolysaccharide (LPS) and TNF activate nuclear factor (NF)-jB in enterocytes. However, it remains elusive whether enterocytes release CXCL2 in response to LPS and TNF via a NF-jB-dependent pathway and whether this involves the endogenous production of TNF and PAF. In this study, we found that TNF and LPS markedly induced CXCL2 gene expression in IEC-6 cells, TNF within 30 min, peaking at 45 min, while LPS more slowly, peaking after 2 hr. TNF-and LPS-induced CXCL2 gene expression and protein release were completely blocked by pyrrolidine dithiocarbamate (PDTC) and helenalin, two potent NF-jB inhibitors. NEMO-binding domain peptide, a specific inhibitor of inhibitor protein jB kinase (IKK) activation, a major upstream kinase mediating NF-jB activation, significantly blocked CXCL2 gene expression and protein release induced by LPS. WEB2170 (PAF antagonist) and anti-TNF antibodies had no effect on LPS-induced CXCL2 expression. In conclusion, CXCL2 gene is expressed in enterocytes in response to both TNF and LPS. LPS-induced CXCL2 expression is dependent on NF-jB activation via the IKK pathway. The effect of LPS is independent of endogenous TNF and PAF.

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Section: Discussionmentioning

confidence: 99%

“…(PAF), 3 a potent endogenous phospholipid. NF-jB is a central transcription factor regulating the transcription of many pro-inflammatory cytokines, chemokines and adhesion molecules.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

Plaen¹,

Han²,

Liu³

et al. 2006

Immunology

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“…Frozen small intestines were ground into powder with a mortar in liquid nitrogen and nuclear extracts obtained following a standard protocol (11). For fetal tissues, two (E20) to three (E18-19) specimens were processed together to obtain sufficient amounts of nuclear extracts.…”

Section: Methodsmentioning

confidence: 99%

“…The dimers of NF-B mostly found in intestinal tissues are p50-p50 and p50-p65 (11,12). NF-B is constitutively present in the cytoplasm of most cells, binding to inhibitory proteins named IB.…”

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confidence: 99%

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

et al. 2007

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Necrotizing enterocolitis (NEC) is a major cause of morbidity and death in premature infants. NEC is associated with increased levels of pro-inflammatory cytokines in plasma and tissues that are regulated by the transcription factor nuclear factor-B (NF-B). It remains unknown, however, whether NF-B mediates injury in neonatal NEC. We therefore examined the activation status of NF-B perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-B is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-B remains strongly activated at both d 1 and d 2 in stressed animals, and this is accompanied by a significant decrease in the levels of the endogenous NF-B inhibitor protein IB␣ and IB␤ at d 2. To determine the importance of elevated NF-B activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream IB kinase (IKK). NBD but not a control peptide decreased mortality and bowel injury in this model, supporting the hypothesis that bowel injury in NEC results from elevated NF-B activity. Our findings therefore lead us to conclude that selective NF-B inhibition represents a promising therapeutic strategy for NEC.

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“…It is the major factor responsible for endotoxin-induced diarrhoea [5,37] and necrotizing enterocolitis in the newborn [38]. PAF probably promotes inflammation via multiple mechanisms, including production and release of pro-inflammatory cytokines such as IL-8, TNFα and IL-1β [9,10,39], and activation of MAPK and NF-κB [8,40]. The increased cytokines may in turn stimulate the release of PAF [41], creating a positive feedback loop in accelerating the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

Nilsson

Jönsson

et al. 2006

Biochemical Journal

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Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [ 3 H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn 2+ . The activity was abolished by site mutation of the predicted metalbinding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V max for PAF hydrolysis was 374 µmol · h −1 · (mg of protein) −1 . The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.

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Intestinal NF-κB is activated, mainly as p50 homodimers, by platelet-activating factor

Cited by 47 publications

References 29 publications

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

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