scholarly journals Immunomodulatory Effects of Voriconazole on Monocytes Challenged with Aspergillus fumigatus: Differential Role of Toll-Like Receptors

2008 ◽  
Vol 52 (9) ◽  
pp. 3301-3306 ◽  
Author(s):  
Maria Simitsopoulou ◽  
Emmanuel Roilides ◽  
Fotini Paliogianni ◽  
Christodoulos Likartsis ◽  
John Ioannidis ◽  
...  
Keyword(s):  
Protein Expression ◽  
Aspergillus Fumigatus ◽  
Immunomodulatory Effect ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Genes Encoding ◽  
Mrna And Protein Expression

ABSTRACT Voriconazole (VRC) has activity against Aspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC and A. fumigatus hyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes than Aspergillus alone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response to A. fumigatus hyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes against A. fumigatus hyphae. Both A. fumigatus hyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-α) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF-α to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-κB was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-κB than hyphae did, treatment with the combination of the two factors induced the greatest NF-κB expression. The pronounced profile of TLR2 signaling, TNF-α expression, and NF-κB activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response to A. fumigatus.

scholarly journals Involvement of CD14 and Toll-Like Receptors in Activation of Human Monocytes by Aspergillus fumigatus Hyphae

2001 ◽  
Vol 69 (4) ◽  
pp. 2402-2406 ◽  
Author(s):  
J. E. Wang ◽  
A. Warris ◽  
E. A. Ellingsen ◽  
P. F. Jørgensen ◽  
T. H. Flo ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Aspergillus Fumigatus ◽  
Human Blood ◽  
Fungal Infections ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Toll Like Receptors ◽  
Necrosis Factor Alpha ◽  
Tnf Α

ABSTRACT Invasive fungal infections represent an increasing problem associated with high mortality. The present study was undertaken to identify leukocyte subsets that are activated by hyphal fragments in a whole-human-blood model, as well as to examine the involvement of CD14 and Toll-like receptors (TLRs) in activation of monocytes by hyphae. Incubation of whole human blood with hyphal fragments fromAspergillus fumigatus and Scedosporium prolificans for 6 h caused induction of mRNAs for tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 in T cells, B cells, and monocytes, but not in granulocytes, as analyzed by reverse transcription-PCR with mRNA isolated from very pure populations of these leukocyte subsets. In primary adherent human monocytes, induction of TNF-α by hyphal fragments was dependent on plasma. Heat treatment of plasma at 56°C for 30 min strongly reduced the ability of plasma to prime for activation. Pretreatment of human monocytes with different concentrations (1, 3, and 10 μg/ml) of monoclonal antibody (MAb) HTA125 (anti-TLR4) or MAb 18D11 (anti-CD14) for 30 min inhibited the release of TNF-α induced by hyphal fragments in a dose-dependent manner. Maximal inhibitions of 35 and 70% were obtained with 10 μg of HTA125 and 18D11 per ml, respectively. In contrast, pretreatment with MAb TL2.1 (anti-TLR2) did not affect signaling induced by hyphae. Pretreatment with the lipid A antagonist B975 blocked lipopolysaccharide signaling but did not inhibit TNF-α production induced by hyphal fragments. Our results suggest that T cells, B cells, and monocytes are involved in the innate immune response to invasive fungal pathogens and that serum components are relevant for activation of monocytes by hyphae. CD14 and TLR4 may be involved in signaling of Aspergillus hyphae in monocytes, but further studies to elucidate this issue are warranted.

scholarly journals Differential Immune Phenotypes in Human Monocytes Induced by Non-Host-AdaptedSalmonella entericaSerovar Choleraesuis and Host-AdaptedS. Typhimurium

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Hiba Ibrahim ◽  
Basim Askar ◽  
Scott Hulme ◽  
Peter Neilson ◽  
Paul Barrow ◽  
...  
Keyword(s):  
High Serum ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Human Sepsis ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Serovar Typhimurium ◽  
Factor Alpha ◽  
High Production

ABSTRACTWe studied the effects of twoSalmonella entericaserovar Typhimurium (host-adapted) strains (14028 and 4/74) and threeS. Choleraesuis (non-host-adapted) strains (A50, A45, and B195) in human monocytes between 2 and 24 h postinfection (p.i.) to investigate whether differences in immune response may explain the much higher prevalence of sepsis in individuals infected withS. Choleraesuis. Both serovars significantly increased the production of cytokines associated with acute sepsis (tumor necrosis factor alpha [TNF-α], interleukin β [IL-β], and IL-6), but temporal differences occurred between these serovars and between differentS. Choleraesuis strains. Generally, allS. Choleraesuis strains induced significantly higher production of inflammatory cytokines thanS. Typhimurium strains (P < 0.01 to 0.05). AllS. Choleraesuis strains very significantly increased IL-10 production by monocytes at 6 and 24 h p.i. in comparison toS. Typhimurium strains (P< 0.01). In addition, ∼80% of monocytes were viable at 24 h p.i. withS. Choleraesuis A50, compared to only ∼40% followingS. Typhimurium infection. UsingS. Typhimurium 14028 andS. Choleraesuis A50 as examples of these two serovars, we also showed differential expression of genes within the Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) (JAK/STAT) pathway via quantitative PCR (qPCR) microarray analysis. High serum IL-10 concentration and monocyte survival have been reported as markers of the development of human sepsis. We therefore conclude that high production of IL-10 by monocytes may, in part, explain the greater propensity forS. Choleraesuis to induce human sepsis and that this may be greater in strains such as A50, which induces both high IL-10 production and monocyte survival.

scholarly journals Loss of Ability To Self-Heal Malaria upon Taurine Transporter Deletion

2010 ◽  
Vol 78 (4) ◽  
pp. 1642-1649 ◽  
Author(s):  
Denis Delić ◽  
Ulrich Warskulat ◽  
Elena Borsch ◽  
Saad Al-Qahtani ◽  
Saleh Al-Quraishi ◽  
...  
Keyword(s):  
Multiorgan Failure ◽  
Taurine Transporter ◽  
Necrosis Factor Alpha ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Taurine Deficiency ◽  
Genes Encoding ◽  
Peak Parasitemia ◽  
Factor Alpha ◽  
Oxide Synthase

ABSTRACT Deletion of the taurine transporter gene (taut) results in lowered levels of taurine, the most abundant amino acid in mammals. Here, we show that taut − / − mice have lost their ability to self-heal blood-stage infections with Plasmodium chabaudi malaria. All taut − / − mice succumb to infections during crisis, while about 90% of the control taut+/+ mice survive. The latter retain unchanged taurine levels even at peak parasitemia. Deletion of taut, however, results in the lowering of circulating taurine levels from 540 to 264 μmol/liter, and infections cause additional lowering to 192 μmol/liter. Peak parasitemia levels in taut − / − mice are approximately 60% higher than those in taut+/+ mice, an elevation that is associated with increased systemic tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) levels, as well as with liver injuries. The latter manifest as increased systemic ammonia levels, a perturbed capacity to entrap injected particles, and increased expression of genes encoding TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), NF-κB, and vitamin D receptor (VDR). Autopsy reveals multiorgan failure as the cause of death for malaria-infected taut − / − mice. Our data indicate that taut-controlled taurine homeostasis is essential for resistance to P. chabaudi malaria. Taurine deficiency due to taut deletion, however, impairs the eryptosis of P. chabaudi-parasitized erythrocytes and expedites increases in systemic TNF-α, IL-1β, and ammonia levels, presumably contributing to multiorgan failure in P. chabaudi-infected taut − / − mice.

scholarly journals Alopecia in Harlequin mutant mice is associated with reduced AIF protein levels and expression of retroviral elements

2020 ◽  
Author(s):  
Maik Hintze ◽  
Sebastian Griesing ◽  
Marion Michels ◽  
Birgit Blanck ◽  
Lena Wischhof ◽  
...  
Keyword(s):  
Hair Growth ◽  
Transcriptional Regulators ◽  
Mutant Mice ◽  
Wild Type ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Keratinocyte Cell ◽  
Apoptosis Inducing Factor ◽  
Hair Cortex

AbstractWe investigated the contribution of apoptosis-inducing factor (AIF), a key regulator of mitochondrial biogenesis, in supporting hair growth. We report that pelage abnormalities developed during hair follicle (HF) morphogenesis in Harlequin (Hq) mutant mice. Fragility of the hair cortex was associated with decreased expression of genes encoding structural hair proteins, though key transcriptional regulators of HF development were expressed at normal levels. Notably, Aifm1 (R200 del) knockin males and Aifm1(R200 del)/Hq females showed minor hair defects, despite substantially reduced AIF levels. Furthermore, we cloned the integrated ecotropic provirus of the Aifm1Hq allele. We found that its overexpression in wild-type keratinocyte cell lines led to down-regulation of HF-specific Krt84 and Krtap3-3 genes without altering Aifm1 or epidermal Krt5 expression. Together, our findings imply that pelage paucity in Hq mutant mice is mechanistically linked to severe AIF deficiency and is associated with the expression of retroviral elements that might potentially influence the transcriptional regulation of structural hair proteins.

scholarly journals The Genes Encoding Small Leucine-Rich Proteoglycans Undergo Differential Expression Alterations in Colorectal Cancer, Depending on Tumor Location

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2002
Author(s):  
Maria Pilar Solis-Hernandez ◽  
Carla Martín ◽  
Beatriz García ◽  
Natalia Pérez-López ◽  
Yolanda García-Mesa ◽  
...  
Keyword(s):  
Protein Expression ◽  
Survival Data ◽  
Tumor Cell Line ◽  
Tumor Location ◽  
Anatomical Location ◽  
Cell Interior ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Descending Colon

Small leucine-rich proteoglycans (SLRPs) regulate different processes and undergo significant alterations in various diseases. Colon carcinomas (CCs) are heterogeneous pathologies with important clinical and molecular differences depending on their location, which makes it interesting to analyze the alterations in SLRPs in right- and left-sided tumors (RS- and LSCCs). SLRP transcription levels were studied in 32 CCs using qPCR compared to healthy colon mucosae samples from the same patients, 20 of them from LSCCs and the remaining 12 from RSCCs. Protein expression of genes with significant differences in their transcriptions was analyzed by immunohistochemistry. The alterations observed were related to survival data. The arrangement of transcription of SLRPs was quite similar in ascending and descending colon, but RS- and LSCCs displayed different patterns of alteration, with a greater number of deregulations occurring in the latter. The analysis of protein expression also indicated changes in the location of these molecules, largely moving to the cell interior. While podocan underexpression showed a trend toward better outcomes, no differences were observed in terms of overall survival. In vitro studies using the HT29 tumor cell line suggest that deregulation of SLRPs could affect cell proliferation. SLRPs constitute new differential markers of RS- and LSCCs, showing differences dependent on the anatomical location of the tumor.

scholarly journals Neuroprotective effects of eugenol against aluminiuminduced toxicity in the rat brain

2017 ◽  
Vol 68 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Mahmoud M. Said ◽  
Marwa M. Abd Rabo
Keyword(s):  
Total Antioxidant Status ◽  
Basal Diet ◽  
Acetylcholinesterase Activity ◽  
Aluminium Chloride ◽  
Neuroprotective Effects ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Total Antioxidant ◽  
Male Wistar Rats

AbstractAluminium (Al) is a neurotoxic metal that contributes to the progression of several neurodegenerative diseases. The aim of the present study was to evaluate the protective effect of dietary eugenol supplementation against aluminium (Al)- induced cerebral damage in rats. Male Wistar rats were divided into four groups: normal controls, rats fed a diet containing 6,000 μg g-1eugenol, rats intoxicated daily with aluminium chloride (84 mg kg-1body weight) p. o. and fed either a basal diet or a eugenol-containing diet. Daily oral administration of Al for four consecutive weeks to rats significantly reduced brain total antioxidant status (TAS) (11.42±0.31 μmol g-1tissue, p<0.001) with a subsequent significant enhancement of lipid peroxidation (MDA) (32.55±1.68 nmol g-1tissue, p<0.002). In addition, Al enhanced brain acetylcholinesterase activity (AChE) (46.22±4.90 U mg-1protein, p<0.001), tumour necrosis factor alpha (TNF-α) (118.72±11.32 pg mg-1protein, p<0.001), and caspase 3 (Casp-3) (8.77±1.26 ng mg-1protein, p<0.001) levels, and in contrast significantly suppressed brain-derived neurotrophic factor (BDNF) (82.74±14.53 pg mg-1protein, p<0.002) and serotonin (5-HT) (1.54±0.12 ng mg-1tissue, p<0.01) levels. Furthermore, decreased glial fibrillary acidic protein (GFAP) immunostaining was noticed in the striatum of Al-intoxicated rats, compared with untreated controls. On the other hand, co-administration of dietary eugenol with Al intoxication restored brain BDNF (108.76±2.64 pg mg-1protein) and 5-HT (2.13±0.27 ng mg-1tissue) to normal levels, enhanced brain TAS (13.43±0.24 μmol g-1tissue, p<0.05), with a concomitant significant reduction in TNF-α (69.98±4.74 pg mg-1protein) and Casp-3 (3.80±0.37 ng mg-1protein) levels (p<0.001), as well as AChE activity (24.50±3.25 U mg-1protein, p<0.001), and increased striatal GFAP immunoreactivity, compared with Al-treated rats. Histological findings of brain tissues verified biochemical data. In conclusion, eugenol holds potential as a neuroprotective agent through its hydrophobic, antioxidant, and anti-apoptotic properties, as well as its neurotrophic ability against Al-induced brain toxicity in rats.

scholarly journals High-Affinity Interaction between Gram-Negative Flagellin and a Cell Surface Polypeptide Results in Human Monocyte Activation

2000 ◽  
Vol 68 (10) ◽  
pp. 5525-5529 ◽  
Author(s):  
Patrick F. McDermott ◽  
Federica Ciacci-Woolwine ◽  
James A. Snipes ◽  
Steven B. Mizel
Keyword(s):  
Cell Surface ◽  
Mutational Analysis ◽  
Hypervariable Region ◽  
Gram Negative Bacteria ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Potent Inducer ◽  
Gram Negative ◽  
High Affinity ◽  
Tnf Α

ABSTRACT Flagella from diverse gram-negative bacteria induce tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) synthesis by human monocytes (F. Ciacci-Woolwine, P. F. McDermott, and S. B. Mizel, Infect. Immun. 67:5176–5185, 1999). In this study, we establish that purified flagellin (FliC or FljB), the major filament protein from Salmonella enterica serovar Enteritidis,S. enterica serovar Typhimurium, and Pseudomonas aeruginosa, is an extremely potent inducer of TNF-α production by human monocytes and THP-1 myelomonocytic cells. Fifty percent of maximal TNF-α production (EC50) was obtained with 1.5 × 10−11 M flagellin (0.75 ng/ml). Mutagenesis studies revealed that the central hypervariable region of flagellin is essential for the TNF-α-inducing activity of the protein. Although less active than the wild-type protein, a Salmonellaflagellin mutant composed of only the central hypervariable region retained substantial TNF-α-inducing activity at nanomolar concentrations. In contrast, the conserved amino- and carboxy-terminal regions are inactive. Mutational analysis of the hypervariable region revealed that it contains two equally active TNF-α-inducing domains. The ability of THP-1 cells to respond to purified flagellins is dramatically reduced by mild trypsin treatment of the cells. Taken together, our results demonstrate that the cytokine-inducing activity of flagellins from gram-negative bacteria results from the interaction of these proteins with high-affinity cell surface polypeptide receptors on monocytes.

scholarly journals Immune Responses of Human Immature Dendritic Cells Can Be Modulated by the Recombinant Aspergillus fumigatus Antigen Aspf1

2009 ◽  
Vol 16 (10) ◽  
pp. 1485-1492 ◽  
Author(s):  
Michael Ok ◽  
Jean Paul Latgé ◽  
Carina Baeuerlein ◽  
Frank Ebel ◽  
Markus Mezger ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aspergillus Fumigatus ◽  
Organ Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Cytokines And Chemokines ◽  
Expression Of Genes ◽  
Immature Dendritic Cells ◽  
Genes Encoding ◽  
Solid Organ Transplant Recipients

ABSTRACT Invasive aspergillosis is a significant cause of morbidity and mortality in patients after stem cell transplantation, in solid organ transplant recipients, and in patients with hematological malignancies. The interactions between human immature dendritic cells (iDCs) and Aspergillus fumigatus antigens are widely uncharacterized. We analyzed the immune response of iDCs to different recombinant A. fumigatus antigens (Aspf1 and Crf1). One of these antigens, the 18-kDa RNase Aspf1, triggered the increased level of expression of genes encoding proinflammatory cytokines and chemokines, and augmented the activation of NFκB and the apoptosis of iDCs. Furthermore, by fluorescence microscopy, we could demonstrate that in the first 3 h a major portion of Aspf1 accumulates on the cell surface. Finally, we could show an increased segregation of cytokines and chemokines after the stimulation of iDCs by an Aspf1 deletion mutant strain of A. fumigatus.

scholarly journals Effect of adalimumab on the expression of genes encoding TNF-α signal paths in skin fibroblasts in vitro

2018 ◽  
Vol 35 (4) ◽  
pp. 413-422 ◽  
Author(s):  
Dominika Wcisło-Dziadecka ◽  
Joanna Gola ◽  
Beniamin Grabarek ◽  
Urszula Mazurek ◽  
Ligia Brzezińska-Wcisło ◽  
...  
Keyword(s):  
Skin Fibroblasts ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Genes Encoding

scholarly journals Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents the Inflammatory Response in a Ligature-Induced Peri-Implantitis Model: A Canine Study

2018 ◽  
Vol 49 (2) ◽  
pp. 610-625 ◽  
Author(s):  
Chun-Yan He ◽  
Li-Peng Jiang ◽  
Cheng-Yue Wang ◽  
Yue Zhang
Keyword(s):  
Inflammatory Response ◽  
Protein Expression ◽  
Quantitative Polymerase Chain Reaction ◽  
Pyrrolidine Dithiocarbamate ◽  
Mrna Levels ◽  
Periodontal Ligament Fibroblasts ◽  
Necrosis Factor Alpha ◽  
Periodontal Tissues ◽  
Periodontal Inflammation ◽  
Tnf Α

Background/Aims: The roles of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in peri-implantitis are unclear. Here, we used a canine model of peri-implantitis to explore the effects of inhibiting NF-κB with pyrrolidine dithiocarbamate (PDTC) on the inflammatory response in ligature-induced peri-implantitis. Methods: After successfully establishing the peri-implantitis model, beagles were randomly assigned to normal, model or PDTC groups. ELISA tests were used to determine the levels of interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). Immunohistochemistry was employed to assess the expression of NF-κB p65. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the mRNA levels of TLR4 and NF-κB p65, and western blot analysis was used to measure the protein levels of TLR4 in periodontal tissues from each group. Periodontal ligament fibroblasts (PDLFs) were cultured and subsequently classified into PDLF normal, PDLF model, PDLF LPS, PDLF PDTC, and PDLF LPS + PDTC groups. An immunofluorescence assay was used to measure the expression level of NF-κB p65. The CCK-8 assay and flow cytometry were performed to evaluate cell proliferation and apoptosis. Results: The in vitro results indicated that NF-κB p65 and TLR4 were upregulated in canine periodontal tissues, and PDTC could suppress the expression levels of NF-κB p65 and TLR4. Inflammation could increase TLR4 protein expression in canine periodontal tissue, and PDTC could inhibit the inflammation-induced increase in TLR4 protein expression. These results revealed that PDTC could reverse the LPS-induced increases in the levels of IL-1, IL-6, IL-8 and TNF-α. In vivo, the results demonstrated that PDTC inhibited the LPS-induced NF-κB p65 upregulation, and PDTC could reverse the inhibitory effect of the PDLF model + LPS on the proliferation of periodontal fibroblasts. The results also showed that in the PDLF model, LPS promoted PDLF apoptosis by inducing implant periodontitis in canines, but PDTC inhibited the PDLF apoptosis and relieved implant periodontitis in canines. Conclusion: Based on our results, we concluded that PDTC can inhibit the expression of NF-κB and alleviate the inflammatory response induced by LPS, thereby preventing periodontal inflammation and reducing the development of peri-implantitis.

Sign in / Sign up

Export Citation Format

Share Document