scholarly journals Cilostazol Suppresses IL-23 Production in Human Dendritic Cells via an AMPK-Dependent Pathway

2016 ◽  
Vol 40 (3-4) ◽  
pp. 499-508 ◽  
Author(s):  
Quanxing Shi ◽  
Zhao Yin ◽  
Peilin Liu ◽  
Bei Zhao ◽  
Zhong Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Western Blotting ◽  
Human Monocyte ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Compound C ◽  
Human Dendritic Cells ◽  
Dependent Pathway

Background/Aims: Cilostazol has been previously demonstrated to inhibit IL-23 production in human synovial macrophages via a RhoA/ROCK-dependent pathway. However, whether cilostazol affects IL-23 production in human dendritic cells remains largely unknown. The present study was designed to investigate this question and elucidate the possible underlying mechanisms. Methods: Human monocyte-derived dendritic cells (mo-DCs) were pretreated with or without cilostazol and then incubated with zymosan. Enzyme-linked immunosorbent assay (ELISA) and real time PCR analyses were used to measure IL-23 protein expression and RNA levels, respectively, whereas Western blotting was used to measure the expression and phosphorylation level of AMPK. Results: Our results demonstrated that cilostazol suppressed zymosan-induced IL-23 protein production in a concentration dependent manner without affecting dendritic cell viability. In addition, it was found that cilostazol suppressed the expression of the p19 and p40 subunits of IL-23. Moreover, cilostazol mimicked the effect of the AMPK agonist A-769662, as demonstrated by the fact that IL-23 production was also inhibited by A-769662, and the effect of cilostazol on IL-23 production was blocked by the AMPK antagonist Compound C. More importantly, Western blotting demonstrated that cilostazol led to an increased phosphorylation of AMPK. Conclusion: Collectively, our data suggest that cilostazol inhibits the production of IL-23 in human mo-DCs, potentially via the activation of AMPK. This suggests that cilostazol could be an effective anti-inflammatory agent in IL-23- and dendritic cell-related diseases.

scholarly journals PGE2 Elevates IL-23 Production in Human Dendritic Cells via a cAMP Dependent Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Quanxing Shi ◽  
Zhao Yin ◽  
Bei Zhao ◽  
Fei Sun ◽  
Haisheng Yu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Concentration Dependent Manner ◽  
Underlying Mechanisms ◽  
Species Specific ◽  
Human Dendritic Cells ◽  
Dependent Pathway ◽  
Cyclase Activator

PGE2 elevates IL-23 production in mouse dendritic cells while inhibits IL-23 production in isolated human monocytes. Whether this differential effect of PGE2 on IL-23 production is cell-type- or species-specific has not been investigated in detail. The present study was designed to investigate the effect of PGE2 on IL-23 production in human DCs and the possible underlying mechanisms. Human monocytes derived dendritic cells (Mo-DCs) were pretreated with or without PGE2. Then the cells were incubated with zymosan. Our results demonstrated that PGE2 promoted zymosan-induced IL-23 production in a concentration dependent manner. In addition, it was found that PGE2 is also able to elevate MyD88-mediated IL-23 p19 promoter activity. More importantly, ELISA data demonstrated that db-cAMP, a cAMP analog, and forskolin, an adenylate cyclase activator, can mimic the effect of PGE2 on zymosan-induced IL-23 production, and rp-cAMP, a protein kinase A (PKA) inhibitor, can block the effect of PGE2. Moreover, PGE2 can increase zymosan-induced expression of the mRNA levels of both p19 and p40 subunits, which was mimicked by db-cAMP and forskolin. Our data suggest that PGE2 elevates the production of IL-23 in human Mo-DCs via a cAMP dependent pathway.

scholarly journals Candida albicans Is Phagocytosed, Killed, and Processed for Antigen Presentation by Human Dendritic Cells

2001 ◽  
Vol 69 (11) ◽  
pp. 6813-6822 ◽  
Author(s):  
Simon L. Newman ◽  
Angela Holly
Keyword(s):  
Dendritic Cells ◽  
Candida Albicans ◽  
Invasive Fungal Disease ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Dendritic Cells

ABSTRACT Candida albicans is a component of the normal flora of the alimentary tract and also is found on the mucocutaneous membranes of the healthy host. Candida is the leading cause of invasive fungal disease in premature infants, diabetics, and surgical patients, and of oropharyngeal disease in AIDS patients. As the induction of cell-mediated immunity to Candida is of critical importance in host defense, we sought to determine whether human dendritic cells (DC) could phagocytose and degradeCandida and subsequently present Candidaantigens to T cells. Immature DC obtained by culture of human monocytes in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 phagocytosed unopsonized Candida in a time-dependent manner, and phagocytosis was not enhanced by opsonization of Candida in serum. Like macrophages (Mφ), DC recognized Candida by the mannose-fucose receptor. Upon ingestion, DC killed Candida as efficiently as human Mφ, and fungicidal activity was not enhanced by the presence of fresh serum. Although phagocytosis ofCandida by DC stimulated the production of superoxide anion, inhibitors of the respiratory burst (or NO production) did not inhibit killing of Candida, even when phagocytosis was blocked by preincubation of DC with cytochalasin D. Further, although apparently only modest phagolysosomal fusion occurred upon DC phagocytosis of Candida, killing ofCandida under anaerobic conditions was almost equivalent to killing under aerobic conditions. Finally, DC stimulatedCandida-specific lymphocyte proliferation in a concentration-dependent manner after phagocytosis of both viable and heat-killed Candida cells. These data suggest that, in vivo, such interactions between DC and C. albicans may facilitate the induction of cell-mediated immunity.

scholarly journals Clostridial C3 Toxins Enter and Intoxicate Human Dendritic Cells

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 563
Author(s):  
Maximilian Fellermann ◽  
Christina Huchler ◽  
Lea Fechter ◽  
Tobias Kolb ◽  
Fanny Wondany ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Stimulated Emission ◽  
Target Cells ◽  
Dependent Manner ◽  
Rho Proteins ◽  
Concentration Dependent Manner ◽  
Monocytic Cells ◽  
Specific Uptake ◽  
Novel Target ◽  
Human Dendritic Cells

C3 protein toxins produced by Clostridium (C.) botulinum and C. limosum are mono-ADP-ribosyltransferases, which specifically modify the GTPases Rho A/B/C in the cytosol of monocytic cells, thereby inhibiting Rho-mediated signal transduction in monocytes, macrophages, and osteoclasts. C3 toxins are selectively taken up into the cytosol of monocytic cells by endocytosis and translocate from acidic endosomes into the cytosol. The C3-catalyzed ADP-ribosylation of Rho proteins inhibits essential functions of these immune cells, such as migration and phagocytosis. Here, we demonstrate that C3 toxins enter and intoxicate dendritic cells in a time- and concentration-dependent manner. Both immature and mature human dendritic cells efficiently internalize C3 exoenzymes. These findings could also be extended to the chimeric fusion toxin C2IN-C3lim. Moreover, stimulated emission depletion (STED) microscopy revealed the localization of the internalized C3 protein in endosomes and emphasized its potential use as a carrier to deliver foreign proteins into dendritic cells. In contrast, the enzyme C2I from the binary C. botulinum C2 toxin was not taken up into dendritic cells, indicating the specific uptake of C3 toxins. Taken together, we identified human dendritic cells as novel target cells for clostridial C3 toxins and demonstrated the specific uptake of these toxins via endosomal vesicles.

scholarly journals AM3 Modulates Dendritic Cell Pathogen Recognition Capabilities by Targeting DC-SIGN

2007 ◽  
Vol 51 (7) ◽  
pp. 2313-2323 ◽  
Author(s):  
Diego Serrano-Gómez ◽  
Rocío T. Martínez-Nuñez ◽  
Elena Sierra-Filardi ◽  
Nuria Izquierdo ◽  
María Colmenares ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Human Monocyte ◽  
Mannose Receptor ◽  
Receptor Expression ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Pathogen Recognition ◽  
Gp120 Protein ◽  
Human Dendritic Cells

ABSTRACT AM3 (Inmunoferon) is an orally effective immunomodulator that influences the regulatory and effector functions of the immune system whose molecular mechanisms of action are mostly unknown. We hypothesized that the polysaccharide moiety of AM3 (IF-S) might affect immune responses by modulating the lectin-dependent pathogen recognition abilities of human dendritic cells. IF-S inhibited binding of viral, fungal, and parasite pathogens by human monocyte-derived dendritic cells in a dose-dependent manner. IF-S specifically impaired the pathogen recognition capabilities of DC-SIGN, as it reduced the attachment of Candida, Aspergillus, and Leishmania to DC-SIGN transfectants. IF-S also inhibited the interaction of DC-SIGN with both its cellular counterreceptor (intercellular adhesion molecule 3) and the human immunodeficiency virus (HIV) type 1 gp120 protein and blocked the DC-SIGN-dependent capture of HIV virions and the HIV trans-infection capability of DC-SIGN transfectants. IF-S promoted DC-SIGN internalization in DCs without affecting mannose receptor expression, and 1D saturation transfer difference nuclear magnetic resonance demonstrated that IF-S directly interacts with DC-SIGN on the cell surface. Therefore, the polysaccharide moiety of AM3 directly influences pathogen recognition by dendritic cells by interacting with DC-SIGN. Our results indicate that DC-SIGN is the target for an immunomodulator and imply that the adjuvant and immunomodulatory actions of AM3 are mediated, at least in part, by alteration of the DC-SIGN functional activities.

scholarly journals Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 617 ◽  
Author(s):  
Helen Freyberger ◽  
Yunxiu He ◽  
Amanda Roth ◽  
Mikeljon Nikolich ◽  
Andrey Filippov
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Adaptive Immune Response ◽  
Human Monocyte ◽  
Activation Markers ◽  
Mhc I ◽  
Adaptive Immune ◽  
Human Dendritic Cells

A potential concern with bacteriophage (phage) therapeutics is a host-versus-phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti-inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it.

scholarly journals CRISPR-based functional genomics in human dendritic cells

2020 ◽  
Author(s):  
Marco Jost ◽  
Amy N. Jacobson ◽  
Jeffrey A. Hussmann ◽  
Giana Cirolia ◽  
Michael A. Fischbach ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Genome Editing ◽  
Individual Variation ◽  
Human Microbiome ◽  
Human Monocyte ◽  
Genetic Screens ◽  
Mucosal Surfaces ◽  
Immune Phenotypes ◽  
Human Dendritic Cells

AbstractDendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR/Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >93% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immune responses. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

scholarly journals Prostaglandin E2 and Tumor Necrosis Factor α Cooperate to Activate Human Dendritic Cells: Synergistic Activation of Interleukin 12 Production

1997 ◽  
Vol 186 (9) ◽  
pp. 1603-1608 ◽  
Author(s):  
Claudia Rieser ◽  
Günther Böck ◽  
Helmut Klocker ◽  
Georg Bartsch ◽  
Martin Thurnher
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Prostaglandin E2 ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Tnf Α ◽  
Human Dendritic Cells ◽  
Necrosis Factor

Interleukin (IL)-12 is a proinflammatory cytokine that contributes to innate resistance and to the development of antigen-specific T cell responses. Among other effects, prostaglandin E2 (PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide (LPS). Here we investigated the effects of PGE2 on human dendritic cells (DCs) which develop in the presence of GM-CSF and IL-4. We demonstrate that in the absence of LPS, PGE2 dose dependently stimulated the production of IL-12 by DCs. Although PGE2 alone stimulated the production of low amounts of IL-12 only, it synergized with tumor necrosis factor (TNF)-α to induce high levels of IL-12 production by DCs. Addition of TNF-α in the absence of PGE2 had no effect on IL-12 production. Conversely, in the presence of LPS, PGE2 inhibited IL-12 production by DCs in a dose-dependent manner. The combination of PGE2 and TNF-α efficiently silenced mannose receptor–mediated endocytosis in DCs and readily induced neo-expression of the CD83 antigen. In addition, the expression of various surface antigens such as major histocompatibility complex class I and II, adhesion, as well as costimulatory molecules was upregulated by this treatment. The effects of PGE2 on IL-12 synthesis and CD83 expression could be mimicked by dibutyryl-cAMP and forskolin, indicating that they were due to the intracellular elevation of cAMP levels. DC treated with PGE2 and TNF-α were most potent in stimulating allogeneic T cell proliferation. Our data demonstrate that PGE2 contributes to the maturation of human DCs and that PGE2 can be a potent enhancer of IL-12 production by human DCs.

Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway

1992 ◽  
Vol 263 (6) ◽  
pp. F1020-F1025 ◽  
Author(s):  
R. M. Edwards ◽  
M. Pullen ◽  
P. Nambi
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Binding Sites ◽  
Soluble Guanylate Cyclase ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
High Affinity ◽  
Dependent Pathway ◽  
Stimulation Of

The effects of endothelins (ET) on guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact rat glomeruli were examined. ET-3 produced a rapid approximately fivefold increase in cGMP levels with the maximum effect occurring at 1 min. The ET-3-induced increase in cGMP accumulation occurred in the absence and presence of 3-isobutyl-1-methylxanthine. ET-1, ET-2, ET-3, and the structurally related toxin, sarafotoxin S6c, all increased glomerular cGMP levels in a concentration-dependent manner and with similar potencies (EC50 approximately 15-30 nM). The L-arginine analogue, N omega-nitro-L-arginine (L-NNA), reduced basal levels of cGMP and also totally inhibited ET-induced increases in cGMP as did methylene blue, an inhibitor of soluble guanylate cyclase. The effect of L-NNA was attenuated by L-arginine but not by D-arginine. The stimulation of cGMP accumulation by ET-3 was dependent on extracellular Ca2+ and was additive to atriopeptin III but not to acetylcholine. The ETA-selective antagonist, BQ 123, had no effect on ET-3-induced formation of cGMP. Glomerular membranes displayed high-affinity (Kd = 130-150 pM) and high-density (approximately 2.0 pmol/mg) binding sites for 125I-ET-1 and 125I-ET-3. ET-1, ET-3, and sarafotoxin S6c displaced 125I-ET-1 binding to glomerular membranes with similar affinities. BQ 123 had no effect on 125I-ET-1 binding. We conclude that ET increases cGMP levels in glomeruli by stimulating the formation of a nitric oxide-like factor that activates soluble guanylate cyclase. This effect of ET appears to be mediated by activation of ETB receptors and may serve to modulate the contractile effects of ET.

scholarly journals Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

2016 ◽  
Vol 113 (47) ◽  
pp. 13438-13443 ◽  
Author(s):  
Longxing Cao ◽  
Haishuang Chang ◽  
Xiangyi Shi ◽  
Chao Peng ◽  
Yongning He
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Intermediate Filaments ◽  
Cell Receptor ◽  
Immune Recognition ◽  
Natural Ligand ◽  
Immune Therapies ◽  
Ph Dependent ◽  
Apoptosis And Necrosis ◽  
Dependent Pathway

Clearance of dead cells is critical for maintaining homeostasis and prevents autoimmunity and inflammation. When cells undergo apoptosis and necrosis, specific markers are exposed and recognized by the receptors on phagocytes. DEC205 (CD205) is an endocytotic receptor on dendritic cells with antigen presentation function and has been widely used in immune therapies for vaccine generation. It has been shown that human DEC205 recognizes apoptotic and necrotic cells in a pH-dependent fashion. However, the natural ligand(s) of DEC205 remains unknown. Here we find that keratins are the cellular ligands of human DEC205. DEC205 binds to keratins specifically at acidic, but not basic, pH through its N-terminal domains. Keratins form intermediate filaments and are important for maintaining the strength of cells and tissues. Our results suggest that keratins also function as cell markers of apoptotic and necrotic cells and mediate a pH-dependent pathway for the immune recognition of dead cells.

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