scholarly journals Human Herpesvirus 6A Induces Dendritic Cell Death and HMGB1 Release without Virus Replication

Pathogens ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Rasmus Gustafsson
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
High Mobility ◽  
Human Herpesvirus ◽  
Human Monocyte ◽  
Hmgb1 Protein ◽  
Innate And Adaptive Immunity ◽  
Th2 Polarization ◽  
Dependent Cell ◽  
Ifn Γ

Human herpesvirus 6A (HHV-6A) is a common virus that has important immunomodulatory effects. Dendritic cells (DC) are key players in innate and adaptive immunity and are implicated in the pathogenesis of many human diseases, including infections. (1) Background: Previous studies have demonstrated suppressive effects of HHV-6A on key DC functions. (2) Methods: human monocyte derived dendritic cells were inoculated with HHV-6A and viral replication, cell viability, and release of high mobility group box 1 (HMGB1) protein from DC and of the cytokines IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ after co-culture with allogenic CD4+ T cells were assessed. (3) Results: Nonproductive infection of HHV-6A in DC leads to titer-dependent cell death and the release of HMGB1 protein, and a Th2 polarization. (4) Conclusion: These immune responses aimed to clear the infection may also imply risks for inflammatory pathologies associated with HHV-6A such as multiple sclerosis.

scholarly journals IFN-γ and R-848 Dependent Activation of Human Monocyte-Derived Dendritic Cells by Neisseria meningitidis Adhesin A

2007 ◽  
Vol 179 (6) ◽  
pp. 3904-3916 ◽  
Author(s):  
Cristina Mazzon ◽  
Barbara Baldani-Guerra ◽  
Paola Cecchini ◽  
Tihana Kasic ◽  
Antonella Viola ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Neisseria Meningitidis ◽  
Human Monocyte ◽  
Ifn Γ

scholarly journals Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Victoria Macht ◽  
Ryan Vetreno ◽  
Natalie Elchert ◽  
Fulton Crews
Keyword(s):  
Cell Death ◽  
High Mobility ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Hmgb1 Protein ◽  
Immature Neurons ◽  
Environmental Milieu ◽  
Binge Ethanol Exposure

Abstract Background Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. Methods Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). Results Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). Conclusions Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3668-3674 ◽  
Author(s):  
Maria C. Kuppner ◽  
Anabel Scharner ◽  
Valeria Milani ◽  
Christoph von Hesler ◽  
Katharina E. Tschöp ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Human Monocyte ◽  
Glutathione Depletion ◽  
Intracellular Glutathione ◽  
Ifn Γ

AbstractIfosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-γ (IFN-γ) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-γ. The decrease in allostimulatory capacity and in IFN-γ and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function. (Blood. 2003;102: 3668-3674)

scholarly journals Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells

2002 ◽  
Vol 195 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Guido Ferlazzo ◽  
Ming L. Tsang ◽  
Lorenzo Moretta ◽  
Giovanni Melioli ◽  
Ralph M. Steinman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cytolytic Activity ◽  
Innate And Adaptive Immunity ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
Ifn Γ ◽  
Human Dendritic Cells

During the innate response to many inflammatory and infectious stimuli, dendritic cells (DCs) undergo a differentiation process termed maturation. Mature DCs activate antigen-specific naive T cells. Here we show that both immature and mature DCs activate resting human natural killer (NK) cells. Within 1 wk the NK cells increase two– to fourfold in numbers, start secreting interferon (IFN)-γ, and acquire cytolytic activity against the classical NK target LCL721.221. The DC-activated NK cells then kill immature DCs efficiently, even though the latter express substantial levels of major histocompatibility complex (MHC) class I. Similar results are seen with interleukin (IL)-2–activated NK cell lines and clones, i.e., these NK cells kill and secrete IFN-γ in response to immature DCs. Mature DCs are protected from activated NK lysis, but lysis takes place if the NK inhibitory signal is blocked by a human histocompatibility leukocyte antigen (HLA)-A,B,C–specific antibody. The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor. However, both immature and mature DCs seem to use a NKp30 independent mechanism to act as potent stimulators for resting NK cells. We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity.

scholarly journals Caspase-1 Mediates Resistance in Murine Melioidosis

2009 ◽  
Vol 77 (4) ◽  
pp. 1589-1595 ◽  
Author(s):  
Katrin Breitbach ◽  
Guang Wen Sun ◽  
Jens Köhler ◽  
Kristin Eske ◽  
Patimaporn Wongprompitak ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Damage ◽  
Bacterial Burden ◽  
Caspase 1 ◽  
In Vivo Experiments ◽  
Cytokine Levels ◽  
Dependent Cell ◽  
Ifn Γ

ABSTRACT The gram-negative rod Burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease which is endemic in tropical and subtropical areas. The bacterium multiplies intracellularly within the cytosol, induces the formation of actin tails, and can spread directly from cell to cell. Recently, it has been shown that B. pseudomallei can induce caspase-1-dependent cell death in macrophages. The aim of the present study was to further elucidate the role of caspase-1 during B. pseudomallei infection. In vivo experiments with caspase-1 −/− mice revealed a high susceptibility to B. pseudomallei challenge. This phenotype was associated with a significantly higher bacterial burden 2 days after infection and decreased gamma interferon (IFN-γ) and interleukin-18 cytokine levels 24 h after infection compared to control animals. caspase-1 −/− bone marrow-derived macrophages (BMM) exhibited strong caspase-3 expression and reduced cell damage compared to wild-type (WT) cells during early B. pseudomallei infection, indicating “classical” apoptosis, whereas WT BMM showed signs of rapid caspase-1-dependent cell death. Moreover, we found that caspase-1 −/− BMM had a strongly increased bacterial burden compared to WT cells 3 h after infection under conditions where no difference in cell death could be observed between both cell populations at this time point. We therefore suggest that caspase-1-dependent rapid cell death might contribute to resistance by reducing the intracellular niche for B. pseudomallei, but, in addition, caspase-1 might also have a role in controlling intracellular replication of B. pseudomallei in macrophages. Moreover, caspase-1-dependent IFN-γ production is likely to contribute to resistance in murine melioidosis.

Identification of an HLA  A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3360-3366 ◽  
Author(s):  
Qiong J. Wang ◽  
Xiao-Li Huang ◽  
Giovanna Rappocciolo ◽  
Frank J. Jenkins ◽  
William H. Hildebrand ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Human Herpesvirus ◽  
Cd8 T Cell ◽  
Lytic Cycle ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Ifn Γ

Abstract Human herpesvirus 8 (HHV-8; Kaposi sarcoma–associated herpesvirus)–specific cytotoxic T-lymphocyte (CTL) and interferon-γ (IFN-γ) responses to proteins produced during the lytic cycle of HHV-8 replication are mediated by HLA class I–restricted, CD8+ T cells. We have characterized the fine specificity of the CD8+ T-cell response to 25 peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for HLA A*0201 binding motifs. One of the 25 HLA A*0201 peptides derived from the glycoprotein B (gB) homolog of Epstein-Barr virus (gB492-500; LMWYELSKI; single-letter amino acid codes) bound to HLA A*0201 and stimulated IFN-γ responses in CD8+ T cells from HHV-8+, HLA A*0201 persons, but not HHV-8–seronegative or non–HLA A*0201 persons. The peptide also induced IFN-γ and CTL reactivity to naturally processed gB protein. The peptide was a major immunogenic epitope of HHV-8 as indicated by induction of IFN-γ responses in peripheral blood mononuclear cells from 5 of 5 HHV-8 seropositive, HLA A*0201 persons when gB492-500 was presented by autologous dendritic cells. T-cell reactivity to gB492-500 was not related to detectable HHV-8 DNA in the blood. These data show that CD8+ T cells recognize an HLA A*0201–restricted epitope for HHV-8 lytic cycle protein gB, particularly when presented by dendritic cells. This epitope may be important in control of HHV-8 infection by CD8+ T cells.

Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO?

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2480-2486 ◽  
Author(s):  
Peter Terness ◽  
Jing-Jing Chuang ◽  
Thomas Bauer ◽  
Lucian Jiga ◽  
Gerhard Opelz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Response ◽  
Human Monocyte ◽  
T Cell Response ◽  
Regulatory Function ◽  
Blood Monocytes ◽  
Indoleamine 2,3 Dioxygenase ◽  
Ifn Γ

AbstractAlthough dendritic cells (DCs) strongly stimulate the immune response, they can also induce unresponsiveness. Recently, a human monocyte-derived DC subpopulation was described that constitutively expresses indoleamine 2,3-dioxygenase (IDO). These DCs were defined as nonadherent CD123+/CC chemokine receptor 6+ (CCR6+) cells that suppress the allogeneic T-cell response. In the present study, we generated nonadherent, mature DCs from human blood monocytes. As expected, in addition to the classic markers, these cells expressed CD123 and CCR6. Reverse transcription–polymerase chain reaction (RT-PCR), however, did not show IDO gene transcription, nor did we detect enzymatic IDO activity. Treating the cells with interferon-γ (IFN-γ) resulted in significant IDO production. Subsequently, we studied the regulatory properties of IDO-producing DCs on autologous and allogeneic T-cell responses. Neither OKT3-stimulated T cells of healthy donors nor myelin basic protein (MBP)–specific T cells of patients with multiple sclerosis (MS) were suppressed by autologous IDO DCs. However, whereas IDOneg DCs supported further stimulation of preactivated MBP-specific T cells of an MS patient, IDOpos DCs had lost this capacity. The allogeneic T-cell response was only marginally suppressed by IDO DCs. Our findings show that nonadherent CD123+/CCR6+ human DCs do not constitutively express IDO, and, even if they express the enzyme after IFN-γ treatment, they possess only limited T-cell regulatory function.

scholarly journals Dengue virus infection promotes translocation of high mobility group box 1 protein from the nucleus to the cytosol in dendritic cells, upregulates cytokine production and modulates virus replication

2009 ◽  
Vol 90 (8) ◽  
pp. 1827-1835 ◽  
Author(s):  
Edwin Kamau ◽  
Ratree Takhampunya ◽  
Tao Li ◽  
Eileen Kelly ◽  
Kristina K. Peachman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dengue Virus ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Cell Types ◽  
Denv Infection ◽  
High Mobility Group ◽  
Regulation Of Transcription ◽  
Hmgb1 Protein ◽  
Necrosis Factor Alpha

High mobility group box 1 (HMGB1) protein functions in regulation of transcription, cellular activation and pro-inflammatory responses. However, the potential role of HMGB1 during viral infection has not been investigated. This study attempted to elucidate whether the HMGB1-mediated inflammatory response contributes to the pathogenesis of dengue virus (DENV) infection. Our data showed that HMGB1 was released at low DENV infection levels (m.o.i. of 1) under non-necrotic conditions by human dendritic cells (DCs). When DENV-infected DCs were co-cultured with autologous T cells, there was increased production of HMGB1 by both cell types. HMGB1 regulated tumour necrosis factor alpha, interleukin (IL)-6, IL-8 and alpha interferon secretion in DENV-infected DCs. Additionally, increased HMGB1 production was associated with reduced DENV replication titres in DCs. These results suggest that HMGB1 production influences DENV infection in susceptible hosts.

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