scholarly journals Human Dendritic Cells Mediate Cellular Apoptosis via Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail)

1999 ◽  
Vol 190 (8) ◽  
pp. 1155-1164 ◽  
Author(s):  
Neil A. Fanger ◽  
Charles R. Maliszewski ◽  
Ken Schooley ◽  
Thomas S. Griffith
Keyword(s):  
Dendritic Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Target Cells ◽  
Functional Difference ◽  
Cellular Apoptosis ◽  
Soluble Trail ◽  
Innate Effector ◽  
Human Dendritic Cells ◽  
Necrosis Factor

TRAIL (TNF-related apoptosis-inducing ligand) is a member of the TNF family that induces apoptosis in a variety of cancer cells. In this study, we demonstrate that human CD11c+ blood dendritic cells (DCs) express TRAIL after stimulation with either interferon (IFN)-γ or -α and acquire the ability to kill TRAIL-sensitive tumor cell targets but not TRAIL-resistant tumor cells or normal cell types. The DC-mediated apoptosis was TRAIL specific, as soluble TRAIL receptor blocked target cell death. Moreover, IFN-stimulated interleukin (IL)-3 receptor (R)α+ blood precursor (pre-)DCs displayed minimal cytotoxicity toward the same target cells, demonstrating a clear functional difference between the CD11c+ DC and IL-3Rα+ pre-DC subsets. These results indicate that TRAIL may serve as an innate effector molecule on CD11c+ DCs for the elimination of spontaneously arising tumor cells and suggest a means by which TRAIL-expressing DCs may regulate or eliminate T cells responding to antigen presented by the DCs.

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.

scholarly journals Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3413-3421 ◽  
Author(s):  
Anjli Kukreja ◽  
Soroosh Radfar ◽  
Ben-Hua Sun ◽  
Karl Insogna ◽  
Madhav V. Dhodapkar
Keyword(s):  
Dendritic Cells ◽  
Tumor Cells ◽  
Cell Fusion ◽  
Bone Disease ◽  
Dominant Role ◽  
Osteoclast Formation ◽  
Cell Contact ◽  
Thrombospondin 1 ◽  
Human Dendritic Cells

Abstract Lytic bone disease in myeloma is characterized by an increase in multinucleate osteoclasts in close proximity to tumor cells. However, the nature of osteoclast precursors and the mechanisms underlying multinuclearity are less understood. Here we show that culture of myeloma cell lines as well as primary myeloma cells with human dendritic cells (DCs) but not monocytes or macrophages leads to spontaneous cell-cell fusion, which then leads to the facile formation of multinucleate bone-resorbing giant cells. Osteoclastogenesis is cell contact dependent, leading to up-regulation of thrombospondin-1 (TSP-1) in DCs. Disruption of CD47–TSP-1 interaction by TSP-1–blocking antibodies or down-regulation of CD47 on tumor cells by RNA interference abrogates tumor-induced osteoclast formation. Blockade of CD47–TSP-1 interactions also inhibits receptor activator for nuclear factor κB ligand- and macrophage colony-stimulating factor–induced formation of osteoclasts from human monocytes. Further, TSP-1 blockade attenuates hypercalcemia induced by parathyroid hormone in vivo. These data point to a role for CD47–TSP-1 interactions in regulating cell-fusion events involved in human osteoclast formation. They also suggest that DCs, known to be enriched in myeloma tumors, may be direct precursors for tumor-associated osteoclasts. Disruption of CD47–TSP-1 interactions or preventing the recruitment of DCs to tumors may provide novel approaches to therapy of myeloma bone disease and osteoporosis.

scholarly journals Interaction of Neisseria meningitidis with Human Dendritic Cells

2001 ◽  
Vol 69 (11) ◽  
pp. 6912-6922 ◽  
Author(s):  
Annette Kolb-Mäurer ◽  
Alexandra Unkmeir ◽  
Ulrike Kämmerer ◽  
Claudia Hübner ◽  
Thomas Leimbach ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Neisseria Meningitidis ◽  
Proinflammatory Cytokines ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Factor Alpha ◽  
Human Dendritic Cells ◽  
Necrosis Factor

ABSTRACT Infection with Neisseria meningitidis serogroup B is responsible for fatal septicemia and meningococcal meningitis. The severity of disease directly correlates with the production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-8. However, the source of these cytokines has not been clearly defined yet. Since bacterial infection involves the activation of dendritic cells (DCs), we analyzed the interaction of N. meningitidis with monocyte-derived DCs. Using N. meningitidis serogroup B wild-type and unencapsulated bacteria, we found that capsule expression significantly impaired neisserial adherence to DCs. In addition, phagocytic killing of the bacteria in the phagosome is reduced by at least 10- to 100-fold. However, all strains induced strong secretion of proinflammatory cytokines TNF-α, IL-6, and IL-8 by DCs (at least 1,000-fold at 20 h postinfection [p.i.]), with significantly increased cytokine levels being measurable by as early as 6 h p.i. Levels of IL-1β, in contrast, were increased only 200- to 400-fold at 20 h p.i. with barely measurable induction at 6 h p.i. Moreover, comparable amounts of cytokines were induced by bacterium-free supernatants of Neisseria cultures containing neisserial lipooligosaccharide as the main factor. Our data suggest that activated DCs may be a significant source of high levels of proinflammatory cytokines in neisserial infection and thereby may contribute to the pathology of meningococcal disease.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals Attenuated Interferon and Proinflammatory Response in SARS-CoV-2–Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation

2020 ◽  
Vol 222 (5) ◽  
pp. 734-745 ◽  
Author(s):  
Dong Yang ◽  
Hin Chu ◽  
Yuxin Hou ◽  
Yue Chai ◽  
Huiping Shuai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Clinical Manifestations ◽  
Cell Types ◽  
Host Responses ◽  
Interferon Response ◽  
Proinflammatory Response ◽  
Innate And Adaptive Immunity ◽  
Virus Shedding ◽  
Human Dendritic Cells ◽  
Productive Virus

Abstract Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.

Exosome: from internal vesicle of the multivesicular body to intercellular signaling device

2000 ◽  
Vol 113 (19) ◽  
pp. 3365-3374 ◽  
Author(s):  
K. Denzer ◽  
M.J. Kleijmeer ◽  
H.F. Heijnen ◽  
W. Stoorvogel ◽  
H.J. Geuze
Keyword(s):  
Dendritic Cells ◽  
B Lymphocyte ◽  
Cytotoxic T Cells ◽  
Membrane Vesicles ◽  
Multivesicular Body ◽  
Cell Types ◽  
Target Cells ◽  
Intercellular Signaling ◽  
Accessory Cells

Exosomes are small membrane vesicles that are secreted by a multitude of cell types as a consequence of fusion of multivesicular late endosomes/lysosomes with the plasma membrane. Depending on their origin, exosomes can play roles in different physiological processes. Maturing reticulocytes externalize obsolete membrane proteins such as the transferrin receptor by means of exosomes, whereas activated platelets release exosomes whose function is not yet known. Exosomes are also secreted by cytotoxic T cells, and these might ensure specific and efficient targeting of cytolytic substances to target cells. Antigen presenting cells, such as B lymphocytes and dendritic cells, secrete MHC class-I- and class-II-carrying exosomes that stimulate T cell proliferation in vitro. In addition, dendritic-cell-derived exosomes, when used as a cell-free vaccine, can eradicate established murine tumors. Although the precise physiological target(s) and functions of exosomes remain largely to be resolved, follicular dendritic cells (accessory cells in the germinal centers of secondary lymphoid organs) have recently been shown to bind B-lymphocyte-derived exosomes at their cell surface, which supports the notion that exosomes play an immunoregulatory role. Finally, since exosomes are derived from multivesicular bodies, their molecular composition might provide clues to the mechanism of protein and lipid sorting in endosomes.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Abstract Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

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