Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2042-2049 ◽  
Author(s):  
Lisa Freeman ◽  
Martin Hewison ◽  
Susan V. Hughes ◽  
Katie N. Evans ◽  
Deborah Hardie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Glucocorticoid Receptors ◽  
Reductase Activity ◽  
Human Monocyte ◽  
Hydroxysteroid Dehydrogenase ◽  
Fine Tuning ◽  
Cd40 Ligation ◽  
And Function ◽  
Human Dendritic Cells

Abstract Glucocorticoids (GCs) exert powerful anti-inflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Immature DCs demonstrate selective enhancement of 11β-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11β-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation.

scholarly journals Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

2000 ◽  
Vol 192 (6) ◽  
pp. 823-834 ◽  
Author(s):  
Hubertus Hochrein ◽  
Meredith O'Keeffe ◽  
Thomas Luft ◽  
Stéphane Vandenabeele ◽  
Raelene J. Grumont ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Human Monocyte ◽  
Interferon Γ ◽  
Th1 Cell ◽  
Cytokine Milieu ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Dendritic Cells ◽  
Stimulating Factor

Interleukin (IL)-12 may be secreted as a bioactive T helper type 1 (Th1) cell–inducing heterodimer, as a monomer, or as an antagonistic homodimer. We analyzed the IL-12 produced by mouse splenic dendritic cells (DCs), human thymic DCs, and cultured human monocyte-derived DCs. IL-12 production required both a microbial or T cell–derived stimulus and an appropriate cytokine milieu. The different IL-12 forms were differentially regulated by the cytokines present rather than the stimulus used. IL-4 alone or together with granulocyte/macrophage colony-stimulating factor or interferon γ effectively enhanced the production of the bioactive heterodimer and selectively reduced the antagonistic homodimer of IL-12. Therefore, IL-4, the major Th2-driving cytokine, provides a negative feedback causing DCs to produce the major Th1-inducing cytokine, bioactive IL-12.

scholarly journals Adenoviruses Activate Human Dendritic Cells without Polarization toward a T-Helper Type 1-Inducing Subset

1999 ◽  
Vol 73 (12) ◽  
pp. 10245-10253 ◽  
Author(s):  
Delphine Rea ◽  
Frederik H. E. Schagen ◽  
Rob C. Hoeben ◽  
Majid Mehtali ◽  
Menzo J. E. Havenga ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Human Monocyte ◽  
Interleukin 12 ◽  
T Helper ◽  
Cell Immunity ◽  
Host Cell Interactions ◽  
Human Dendritic Cells ◽  
Adenovirus Receptor ◽  
Helper Type

ABSTRACT Human monocyte-derived dendritic cells (DC) infected with recombinant adenoviruses (rAd) are promising candidate vaccines for inducing protective immunity against pathogens and tumors. However, since some viruses are known to negatively affect DC function, it is important to investigate the interactions between rAd and DC. We now show that infection by rAd enhances the immunostimulatory capacity of immature human monocyte-derived DC through the upregulation of the costimulatory molecules CD80, CD86, and CD40 and the major histocompatibility complex class I and II molecules. Although rAd infection fails to induce the secretion of interleukin-12 (IL-12) and only marginally induces the expression of the DC maturation marker CD83, it acts in synergy with CD40 triggering in rendering DC fully mature. rAd-infected DC triggered through CD40 produce more IL-12 and are more efficient in eliciting T-helper type 1 responses than DC activated by CD40 triggering only. rAd lacking one or more of the early regions, E1, E2A, E3, and E4, which play an important role in virus-host cell interactions are equally capable of DC activation. Efficient DC infection requires a high multiplicity of infection (>1,000), a fact which can be attributed to the absence of the coxsackievirus and adenovirus receptor on this cell type. Despite the poor ability of DC to be infected by rAd, which may be improved by targeting rAd to alternative DC surface molecules, DC infected with all currently tested rAd constitute potent immunostimulators. Our study provides new insights into the interactions between two highly promising vaccine components, rAd and DC, and indicates that their combination into one vaccine may be very advantageous for the stimulation of T-cell immunity.

Proteasome Inhibitors Affect the Function of Human Dendritic Cells and Induce Caspase-Mediated Apoptosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2229-2229
Author(s):  
Karin von Schwarzenberg ◽  
Alessio Nencioni ◽  
Anita Bringmann ◽  
Lothar Kanz ◽  
Franco Patrone ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Proteasome Inhibitors ◽  
Human Monocyte ◽  
Proteasome Inhibition ◽  
Parp Cleavage ◽  
Induced Apoptosis ◽  
And Function ◽  
Human Dendritic Cells

Abstract Proteasome inhibitors (PI) show antitumor activity against a broad spectrum of human malignancies both in vitro and in vivo. Yet, the consequences of exposure to these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effect of the proteasome inhibitors on human monocyte-derived dendritic cells (DCs). Exposure to PI results in a reduced activation induced DC maturation and cytokine production, inhibition of their migratory capacity and impaired ability to stimulate T-cell responses. These functional and phenotypic alterations were paralleled by a decreased phosphorylation of the MAP kinase member ERK1/2 while not affecting p38. Furthermore, incubation of DC with bortezomib inhibited the expression of nuclear localized transcription factors that were shown to be important for DC differentiation and function like IRF3, Rel-b and c-rel. Addition of PI to culture medium induced apoptosis of differentiated DCs and strongly reduced the yield of viable DCs when given to monocytes before differentiation to DCs was induced. DC apoptosis was accompanied by caspase activation as detected by caspase-3 and PARP cleavage. Cytochrome c cytosolic relocalization was detectable following exposure to bortezomib and was not prevented by caspase inhibition. This points to the mitochondrial damage as to an upstream event in DC apoptosis via proteasome inhibition. While not affecting Bcl-2 levels, bortezomib was found to promote Bax upregulation in DCs, thus providing a possible explanation for mitochondria dysfunction in response to this compound. In conclusion, this study shows that besides the inhibition of Nf-kB bortezomib is affecting several other pivotal signal transduction pathways in human cells and suggests that inhibition of DC function and induction of apoptosis in DCs may represent a mechanism by which bortezomib can affect the immune responses in patients treated with this compound.

scholarly journals 7α-Hydroxytestosterone Affects 11β-Hydroxysteroid Dehydrogenase 1 Direction in Rat Leydig Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 748-754 ◽  
Author(s):  
Guo-Xin Hu ◽  
Qing-Quan Lian ◽  
Bing-Bing Chen ◽  
Pramod V. Prasad ◽  
Narender Kumar ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Developmental Changes ◽  
Rat Testis ◽  
P450 Enzyme ◽  
And Function ◽  
Developing Rat ◽  
Important Enzyme

The cytochrome P450 2A1 (CYP2A1) is a P450 enzyme that catalyzes the metabolism of testosterone. CYP2A1 has been reported to be present in rat testis. However, its developmental changes and function have not been well characterized. The purpose of this study was to measure the abundance of CYP2A1 (Cyp2a1) mRNA in the developing rat testis and Leydig cells and examine the effects of its product, 7α-hydroxytestosterone (7HT), on an important enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that interconverts active corticosterone and inactive 11-dehydrocorticosterone. As detected by real-time PCR, Cyp2a1 was found to be present exclusively in the Leydig cell. CYP2A1 activity in adult Leydig cells was 5-fold higher than those in progenitor or immature Leydig cells. 7HT competitively suppressed 11β-HSD1 oxidase and reductase activities in rat testis microsome with inhibitory constant of 1.2 and 2.9 μm, respectively. In intact Leydig cells, 7HT did not inhibit 11β-HSD1 reductase activity, but it stimulated its reductase activity. Thus, at 100 nm and higher concentrations, 7HT significantly switched 11β-HSD1 oxidoreductase activities toward reductase. The present data shows that 7HT, the product formed by CYP2A1 from testosterone, regulates the direction of 11β-HSD1 activity in rat Leydig cells.

scholarly journals Development and function of human dendritic cells in humanized mice models

2020 ◽  
Vol 125 ◽  
pp. 151-161
Author(s):  
Giorgio Anselmi ◽  
Julie Helft ◽  
Pierre Guermonprez
Keyword(s):  
Dendritic Cells ◽  
Humanized Mice ◽  
And Function ◽  
Human Dendritic Cells

B lymphocytes can regulate the maturation and function of human dendritic cells but are partially inefficient in systemic lupus erythematosus

2012 ◽  
Vol 71 (Suppl 1) ◽  
pp. A34.1-A34
Author(s):  
Ahsen Morva ◽  
Sébastien Lemoine ◽  
Achouak Achour ◽  
Alain Saraux ◽  
Jacques-Olivier Pers ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
B Lymphocytes ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
And Function ◽  
Human Dendritic Cells

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 Inhibition of O-GlcNAc Transferase Alters the Differentiation and Maturation Process of Human Monocyte Derived Dendritic Cells

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3312
Author(s):  
Matjaž Weiss ◽  
Marko Anderluh ◽  
Martina Gobec
Keyword(s):  
Dendritic Cells ◽  
Posttranslational Modification ◽  
Human Monocyte ◽  
T Cell Differentiation ◽  
Maturation Process ◽  
Hla Dr ◽  
Glcnac Transferase ◽  
And Function

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells (moDCs). Our study suggests that inhibition of OGT modulates AKT and MEK/ERK pathways in moDCs. Changes were also observed in the expression levels of relevant surface markers, where reduced expression of CD80 and DC-SIGN, and increased expression of CD14, CD86 and HLA-DR occurred. We also noticed decreased IL-10 and increased IL-6 production, along with diminished endocytotic capacity of the cells, indicating that inhibition of O-GlcNAcylation hampers the transition of monocytes into immature DCs. Furthermore, the inhibition of OGT altered the maturation process of immature moDCs, since a CD14medDC-SIGNlowHLA-DRmedCD80lowCD86high profile was noticed when OGT inhibitor, OSMI-1, was present. To evaluate DCs ability to influence T cell differentiation and polarization, we co-cultured these cells. Surprisingly, the observed phenotypic changes of mature moDCs generated in the presence of OSMI-1 led to an increased proliferation of allogeneic T cells, while their polarization was not affected. Taken together, we confirm that shifting the O-GlcNAcylation status due to OGT inhibition alters the differentiation and function of moDCs in in vitro conditions.

Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2875-2882 ◽  
Author(s):  
Janne Komi ◽  
Olli Lassila
Keyword(s):  
Dendritic Cells ◽  
Human Monocyte ◽  
Functional Differentiation ◽  
Cd40 Ligation ◽  
Treatment And Prevention ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Antigen Presenting ◽  
Stimulating Factor

Dendritic cells (DC) are professional antigen-presenting cells with a unique capacity to initiate and regulate immune responses. Immature CD1a+ DC can be cultured from CD14+monocytes in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in vitro. Results of this study show that the nonsteroidal anti-estrogens toremifene and tamoxifen inhibit this differentiation. In the presence of anti-estrogens the cells lose CD14 expression, but remain CD1a− and clearly have less dendritic processes than immature DC. Functionally, anti-estrogen-treated cells are inferior to immature DC in inducing proliferation of allogeneic T cells and in producing IL-12 p70 protein after CD40 ligation. The expression of the costimulatory molecules CD80 and CD86 is differentially regulated by anti-estrogens during DC differentiation. Furthermore, anti-estrogens are also able to inhibit the terminal maturation of DC. By inhibiting the functional differentiation of DC, anti-estrogens may have a role in the treatment and prevention of autoimmune diseases.

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