Human Oviductal Stromal Fibroblasts, But Not Oviductal Epithelial Cells, Express Toll‐Like Receptor 4: The Site‐Specific Mucosal Immunity of the Human Fallopian Tube against Bacterial Infection
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Abstract:
To evaluate the site-specific immunoregulatory mechanisms against bacterial infection in the human fallopian tubes.We investigated the effects of lipopolysaccharide (LPS) on the production of CXC chemokines by cultured oviductal epithelial cells (OEC) and oviductal stromal fibroblasts (OSF). The expression of Toll-like receptor (TLR) 4 and CD14 protein in OEC and OSF were evaluated. The phosphorylation of the inhibitor kappaB-alpha (IkappaB-alpha) protein after LPS stimulation was also examined.Lipopolysaccharide stimulated the secretion of granulocyte chemotactic protein-2, growth-regulated oncogene-alpha, and epithelial neutrophil activating peptide-78 by OSF, but not by OEC. The phosphorylation of the IkappaB-alpha protein was not detected in OEC after stimulation by LPS, whereas IkappaB-alpha phosphorylation was observed in OSF after stimulation by LPS. The expression of the TLR4 protein and mRNA was detected only in OSF but not in OEC. The expression of CD14 was not detected in either OEC or OSF.These results suggest that epithelial cells and fibroblasts in the human fallopian tube have evolved a unique, site-specific mechanism for recognizing Gram-negative pathogens. The lack of TLR4 in OEC may be important for avoiding a state of unnecessary inflammation that could disrupt the epithelial barrier and cause irreversible tubal scarring.Keywords:
Fallopian tube
Interleukin 8
Toll-like receptor 4 (TLR4), especially expressed on monocytes/macrophages, connects microbial and sterile innate immune activation. Lipopolysaccharide (LPS) from Gram-negative bacteria and several endogenous molecules, among others saturated fatty acids (SFAs), are able to induce signalling through this receptor. Downstream inflammatory cytokines orchestrate the immune response. Our aim was to investigate how long-lasting multifactorial stress affects Gram-negative signalling and search for possible correlations between cytokine production and TLR4 expression or SFA concentration.Eight healthy males were studied during a 7-day ranger-training course with semi-continuous physical strain, together with energy and sleep restrictions. Blood drawn on days 0, 3, 5 and 7 was incubated ex vivo for 6 h with or without LPS 10 ng/mL, whereupon surface expression of TLR4 on CD14⁺ monocytes and supernatant concentrations of inflammatory cytokines (TNF-α, IL-1β and IL-6) were measured. In addition, plasma free fatty acids were quantified.Monocyte TLR4 expression was elevated throughout the course (p < 0.05 vs. baseline). Corresponding results were found for SFAs. The concentration of TNF-α increased significantly on day 3 and thereafter normalized, and a similar pattern was seen for IL-1β. No correlations were found between cytokine concentrations and monocyte TLR4 expression or plasma SFAs.Multifactorial stress significantly affected ex vivo production of TNF-α and monocyte surface expression of TLR4. In addition, mobilization of fat resulted in increased plasma concentrations of SFAs. No associations between inflammatory cytokines and monocyte TLR4 expression or SFAs were found.
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Objective:To investigate the influences of Aβ25-35 on the TLR3 and TLR4 mRNA. Method: NG108-15 cell line was stimulated with Aβ25-35,the supernatant was collected 24 hours later and the inflammatory factors TNF-α and IFN-β were quantitatively measured,the changes in the mRNA expression of TLR3 and TLR4 were detected by real-time PCR. Result:Aβ induced the over-secreting of TNF-α、IFN-β and over-expression of TLR3 and TLR4 mRNA (P 0. 01). Conclusions:Aβ induced the over-secreting of inflammatory factors and over-expression of TLR3 and TLR4,indicating the action of Aβ in causing AD disease might be affiliated with the immune inflammation and the TLRs signaling pathway.
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Abstract LPCAT2 is a lipid-modifying enzyme that co-localises in lipid rafts with TLR4 and regulates macrophage inflammatory response; however, its effect on TLR4 co-receptor–CD14 is unknown. RAW264.7 cells, a common murine macrophage experimental model, were used to study the effect of LPCAT2 on CD14 expression. The expression of LPCAT2 in RAW264.7 cells was silenced using RNA interference and treated with 100ng/ml of various lipopolysaccharide chemotypes. We found that CD14 expression induced by smooth lipopolysaccharide was significantly decreased (p < 0.05) in RAW264.7 macrophages with LPCAT2 silenced. This study suggests that LPCAT2 regulates CD14 gene and protein expression. This implies that LPCAT2 can regulate CD14-dependent cellular activities.
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Neonatal Sepsis
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Objective To explore the effect of LPS on the expression of CD14 and Toll like receptor 4 (TLR4) in rat Kupffer cells (KCs).Methods In the rat KCs stimulated with LPS,the expression of CD14,TLR4,TNFα and IL 6 was detected.Results LPS could obviously up regulated the expression of CD14 and TLR4 in a dose dependent manner (LPS 10?mg/L,CD14/GAPDH=0.73,TLR4/GAPDH=0.63) and time dependent manner (0.5 24.0?h,the expression of CD14 reached the peak during 3 to 6 h,CD14/GAPDH=0.86).The expression of CD14 and TLR4 in KCs stimulated by the active mediators from KCs which had been exposed to LPS 1 h was obviously increased.Conclusion There were a close correlation between LPS or the active mediators from KCs induced by LPS and the expression of CD14,TLR 4.It is implied that the increases of TLR4 and CD14 expression may be induced by LPS in 1 3?h,and later further increases of TLR4 and CD14 expression may be correlated with the cytokines produced by KCs.
Glyceraldehyde 3-phosphate dehydrogenase
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Bacterial endotoxin [lipopolysaccharide (LPS)] is essential for bacterial virulence as it has a biphasic effect which is either harmful and leads to aseptic shock and death or assists the body defense mechanisms as it stimulates B-cells activation. Many studies have noted that LPS do their action through activation of CD14/ TLR4 pathways, which occur mainly in liver cells, including Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells, which are responsible for cytokines releases and shows the good or bad LPS effect.
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Monocyte
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Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and other exogenous and endogenous molecules, and is thought to contribute to defense mechanisms against infections. Our objective was to elucidate the clinical significance of TLR4 in acute infectious diseases by analyzing its sequential expression on CD14+ monocytes. Peripheral blood samples were obtained from 36 patients with acute infectious diseases on admission and after treatment within certain intervals. The TLR4 expression on CD14+ monocytes was analyzed using flow cytometry and was presented as a mean fluorescence intensity (MFI). TLR4 expression during the acute phase of infection was highly enhanced compared to that of normal subjects (MFI: 22.1 vs 8.5). TLR4 expression was promptly reduced to normal levels in parallel with the disease improvement. In patients who died despite treatment, the enhancement of TLR4 expression during the acute phase was less prominent compared to those who survived (MFI: 14.6 vs 23.5) and its sequential change was also subtle. These results indicate that monocytes respond to acute infections by the induction of TLR4 expression and that a poor response may be associated with a poor prognosis.
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Background: LPS sensitivity in the liver significantly worsens the outcome of gram negative sepsis. MD-2 facilitates the recognition of LPS by Toll-like receptor (TLR4). In this study we investigated the changes in TLR4 and MD-2 levels in LPS sensitive livers.
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Abstract The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response.
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