A Distinct Role of Neutrophil Lactoferrin in RelA/p65 Phosphorylation on Ser536 by Recruiting TNF Receptor-Associated Factors to IκB Kinase Signaling Complex
Abstract:The activation of NF-κB by neutrophil lactoferrin (Lf) is regulated via the IκB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IκB. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser536, but not the Ser276 residue, and stimulated the translocation of p65 into the nucleus. Lf was also shown to enhance the association between p65 and CREB-binding protein/p300 in vivo. To elucidate the mechanism by which Lf triggers these signaling p… Show more
“…The transcription factor NF-kB is known to play a central role on the regulation of inflammatory and immune responses and on the control of cell mitosis and apoptosis (45). In opposition to the studies of Conish et al (8), Oh et al (35) reported in neutrophils an activation of NF-B by LF concentration ranging from 20 to 100 g/ml. This suggests that LF can trigger different pathways, depending on the target cells.…”
The aim of the present study was to evaluate the effect of dietary lactoferrin on bone metabolism in vivo using a postmenopausal animal model. We investigated whether bovine lactoferrin (bLF) ingestion could prevent bone loss in ovariectomized mice. Twelve-week-old female C3H mice either ovariectomized or sham operated were fed for 27 wk with the control diet (AIN-93M with 140 g of total milk protein as a protein source per kg of diet). Four groups of ovariectomized mice received diets including different concentrations of bLF (1, 5, 10, or 20 g of total milk protein were replaced by bLF). Ovariectomy induced a decreased uterine weight and a smaller gain of bone mineral density. Immunoreactive bLF was detected in the peripheral blood, and its concentration was related to the amount of bLF ingestion. bLF supplementation to the diet improved bone mineral density (BMD) and femoral failure load in a dose-dependent manner. We confirmed the direct effects of bLF in vitro using established and primary cultures of murine bone cells. Addition of bLF to the culture medium at a concentration of between 1 and 1,000 microg/ml stimulated both cell growth and differentiation of osteoblastic MC3T3 cells while inhibiting the growth of preosteoclastic RAW 267.4 cells. In primary culture of mixed bone cells, an enhanced osteoblast differentiation was associated with an inhibition of osteoclast differentiation at lower bLF concentrations (1-10 microg/ml). In conclusion, these findings suggest that dietary lactoferrin supplementation can have a beneficial effect on postmenopausal bone loss by modulating bone formation and resorption.
“…The transcription factor NF-kB is known to play a central role on the regulation of inflammatory and immune responses and on the control of cell mitosis and apoptosis (45). In opposition to the studies of Conish et al (8), Oh et al (35) reported in neutrophils an activation of NF-B by LF concentration ranging from 20 to 100 g/ml. This suggests that LF can trigger different pathways, depending on the target cells.…”
The aim of the present study was to evaluate the effect of dietary lactoferrin on bone metabolism in vivo using a postmenopausal animal model. We investigated whether bovine lactoferrin (bLF) ingestion could prevent bone loss in ovariectomized mice. Twelve-week-old female C3H mice either ovariectomized or sham operated were fed for 27 wk with the control diet (AIN-93M with 140 g of total milk protein as a protein source per kg of diet). Four groups of ovariectomized mice received diets including different concentrations of bLF (1, 5, 10, or 20 g of total milk protein were replaced by bLF). Ovariectomy induced a decreased uterine weight and a smaller gain of bone mineral density. Immunoreactive bLF was detected in the peripheral blood, and its concentration was related to the amount of bLF ingestion. bLF supplementation to the diet improved bone mineral density (BMD) and femoral failure load in a dose-dependent manner. We confirmed the direct effects of bLF in vitro using established and primary cultures of murine bone cells. Addition of bLF to the culture medium at a concentration of between 1 and 1,000 microg/ml stimulated both cell growth and differentiation of osteoblastic MC3T3 cells while inhibiting the growth of preosteoclastic RAW 267.4 cells. In primary culture of mixed bone cells, an enhanced osteoblast differentiation was associated with an inhibition of osteoclast differentiation at lower bLF concentrations (1-10 microg/ml). In conclusion, these findings suggest that dietary lactoferrin supplementation can have a beneficial effect on postmenopausal bone loss by modulating bone formation and resorption.
“…This phosphorylation event occurs after NF-κB dissociation from its cytoplasmic inhibitor IκB and serves to slow down its export from the nucleus back to the cytosol, thus increasing the amplitude of NF-κB-induced gene transactivation. Ser536 phosphorylation also promotes NF-κB mediated transcription via recruitment of other transcription coactivators such as p300, enlarging the scope of proinflammatory activities [60]. LPG and CPI-GC also induced phosphorylation of ERK1/2, which is activated in macrophages upon trichomonad infection and linked to host cell apoptosis [61].…”
Trichomonas vaginalis causes the most common non-viral sexually transmitted infection linked to increased risk of premature birth, cervical cancer and HIV. This study defines molecular domains of the parasite surface glycoconjugate lipophosphoglycan (LPG) with distinct functions in the host immunoinflammatory response. The ceramide phospho-inositol glycan core (CPI-GC) released by mild acid had Mr of ∼8,700 Da determined by MALDI-TOF MS. Rha, GlcN, Gal and Xyl and small amounts of GalN and Glc were found in CPI-GC. N-acetyllactosamine repeats were identified by endo-β-galactosidase treatment followed by MALDI-MS and MS/MS and capLC/ESI-MS/ MS analyses. Mild acid hydrolysis led to products rich in internal deoxyhexose residues. The CPI-GC induced chemokine production, NF-κB and extracellular signalregulated kinase (ERK)1/2 activation in human cervicovaginal epithelial cells, but neither the released saccharide components nor the lipid-devoid LPG showed these activities. These results suggest a dominant role for CPI-GC in the pathogenic epithelial response to trichomoniasis.
“…In addition to enhanced acetylation of K310, we also show that DC-SCRIPT knockdown leads to enhanced phosphorylation of Ser 536 NFkBp65. Interestingly, it has been shown that enhanced phosphorylation of this specific site is linked to enhanced interaction between NF-kBp65 and p300/CBP (54). Therefore, it is tempting to FIGURE 5.…”
The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.
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