scholarly journals PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells

2006 ◽  
Vol 203 (10) ◽  
pp. 2351-2362 ◽  
Author(s):  
Istvan Szatmari ◽  
Attila Pap ◽  
Ralph Rühl ◽  
Jiang-Xing Ma ◽  
Petr A. Illarionov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Retinoic Acid ◽  
Antigen Presentation ◽  
Cell Activation ◽  
Acid Synthesis ◽  
Inkt Cell ◽  
Peroxisome Proliferator ◽  
Lipid Antigen

Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)γ, indirectly regulates CD1d expression. Here we demonstrate that PPARγ, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARγ-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)α in human DCs, and RARα acutely regulates CD1d expression. The retinoic acid–induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARγ-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.

scholarly journals Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

2011 ◽  
Vol 187 (1) ◽  
pp. 240-247 ◽  
Author(s):  
Britt Nakken ◽  
Tamas Varga ◽  
Istvan Szatmari ◽  
Lajos Szeles ◽  
Adrienn Gyongyosi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Cathepsin D ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Antigen

Induction of Invariant NKT Cell-Dependent Alloreactivity by Administration of G-CSF after Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3499-3499
Author(s):  
Edward S Morris ◽  
Kelli P A MacDonald ◽  
Rachel D Kuns ◽  
Helen M Morris ◽  
Tatjana Banovic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Cell Activation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Inkt Cell ◽  
Allogeneic Bone ◽  
Nkt Cell

Abstract G-CSF is often used to hasten neutrophil recovery following allogeneic bone marrow transplantation (BMT), but the clinical and immunological consequences invoked remain unclear. We examined this in murine models and found that administration of both standard G-CSF and pegylated G-CSF early after BMT significantly increased graft-versus-host disease (GVHD). This effect was seen in the B6 → B6D2F1, BALB/c → B6 and C3H.SW → B6 systems of GVHD to either MHC or multiple minor histocompatibility antigens. This effect was dependent on total body irradiation (TBI) rendering host dendritic cells (DC) responsive to G-CSF by up-regulating their expression of the G-CSF receptor as determined by real-time PCR. This induction of G-CSFR expression was not seen following busulfan (Bu), cyclophosphamide (Cy) or fludarabine. The enhanced GVHD was present when G-CSF was administered to both WT and G-CSFR−/− donors but not G-CSFR−/− recipients, confirming that host signalling was critical for this effect. G-CSF administration after BMT had no effect on inflammatory cytokine generation but enhanced in vivo CTL activity after BMT when administered to WT but not G-CSFR−/−, CD1d−/−, IFNgR−/− or CD40−/− recipients. Furthermore, donor iNKT cell activation was absent in CD11c Diptheria Toxin Receptor recipient transgenic mice depleted of dendritic cells (DC) by diphtheria toxin and treated with G-CSF. Thus, stimulation of host DC by G-CSF subsequently unleashed a cascade of events characterized by CD1d dependent donor iNKT cell activation, IFNg secretion and CD40-dependent amplification of donor CTL function during the effector phase of GVHD. Critically, the detrimental effects of G-CSF on GVHD were present when administered early following TBI conditioning and at a time when residual host APC were still present (day +1), but had no effect when administered at day +8 when host DC were not detectable by phenotypic or functional analysis. This is consistent with the inefficient cross presentation of host Ag within MHC class I by donor DC after BMT. In addition, the administration of G-CSF after Bu/Cy conditioning had no effect, perhaps explaining the conflicting and somewhat controversial clinical studies from the large European and North American BMT registries since TBI conditioning predominated only in the positive European study. These data have major implications for the use of G-CSF in disease states where NKT cell activation may have important effects on outcome and suggest a guide to the safe use of G-CSF after allogeneic BMT.

scholarly journals Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans

2011 ◽  
Vol 208 (4) ◽  
pp. 761-773 ◽  
Author(s):  
Angus Stock ◽  
Sarah Booth ◽  
Vincenzo Cerundolo
Keyword(s):  
Dendritic Cells ◽  
Retinoic Acid ◽  
Immune Responses ◽  
Prostaglandin E2 ◽  
Cell Activation ◽  
Negative Regulator ◽  
B Cell Activation ◽  
Ccr9 Expression

The production of retinoic acid (RA) by dendritic cells (DCs) is critical for the induction of gut-tropic immune responses by driving the expression of intestinal-specific homing receptors, such as α4β7 and CCR9, upon T and B cell activation. However, how RA production is regulated during DC development remains unclear. We describe an unexpected role for prostaglandin E2 (PGE2) as a negative regulator of retinal dehydrogenases (RALDH), the enzymes responsible for RA synthesis. The presence of PGE2 during DC differentiation inhibited RALDH expression in mouse and human DCs, abrogating their ability to induce CCR9 expression upon T cell priming. Furthermore, blocking PGE2 signaling increased the frequency of RALDH+ DCs in vitro, and reducing PGE2 synthesis in vivo promoted the systemic emergence of RA-producing DCs and the priming of CCR9+ T cells in nonintestinal sites such as the spleen. Finally, we found that PGE2 stimulated the expression of the inducible cyclic AMP early repressor, which appears to directly inhibit RALDH expression in DCs, thus providing mechanistic insight into how PGE2 signaling down-modulates RALDH. Given the role of PGE2 in regulating the development of RA-producing DCs, modulating this pathway may prove a novel means to control the development of gut-tropic immune responses.

scholarly journals Response of the Splenic Dendritic Cell Population to Malaria Infection

2004 ◽  
Vol 72 (7) ◽  
pp. 4233-4239 ◽  
Author(s):  
Andrew L. Leisewitz ◽  
Kirk A. Rockett ◽  
Bonginkosi Gumede ◽  
Margaret Jones ◽  
Britta Urban ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cell Population ◽  
T Cell Activation ◽  
Malaria Infection ◽  
Cell Activation ◽  
Splenic Dendritic Cell ◽  
Dendritic Cell Population

ABSTRACT Dendritic cells, particularly those residing in the spleen, are thought to orchestrate acquired immunity to malaria, but it is not known how the splenic dendritic cell population responds to malaria infection and how this response compares with the responses of other antigen-presenting cells. We investigated this question for Plasmodium chabaudi AS infection in C57BL/6 mice. We found that dendritic cells, defined here by the CD11c marker, migrated from the marginal zone of the spleen into the CD4+ T-cell area within 5 days after parasites entered the bloodstream. This contrasted with the results observed for the macrophage and B-cell populations, which expanded greatly but did not show any comparable migration. Over the same time period dendritic cells showed upregulation of CD40, CD54, and CD86 costimulatory molecules that are required for successful T-cell activation. In dendritic cells, the peak intracellular gamma interferon expression (as shown by fluorescence-activated cell sorting) was on day 5, 2 days earlier than the peak expression in B-cells or macrophages. These findings show that splenic dendritic cells are actively engaged in the earliest phase of malarial infection in vivo and are likely to be critical in shaping the subsequent immune response.

scholarly journals Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model

2009 ◽  
Vol 284 (24) ◽  
pp. 16541-16552 ◽  
Author(s):  
Üzen Savas ◽  
Daniel E. W. Machemer ◽  
Mei-Hui Hsu ◽  
Pryce Gaynor ◽  
Jerome M. Lasker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Transgenic Mice ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Peroxisome Proliferator ◽  
Sexually Dimorphic ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver And Kidney

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

Otx2andGbx2are required for refinement and not induction of mid-hindbrain gene expression

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 4979-4991 ◽  
Author(s):  
James Y. H. Li ◽  
Alexandra L. Joyner
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Mouse Embryos ◽  
Anterior Region ◽  
Spatial Domains ◽  
Cerebellum Development

Otx2 and Gbx2 are among the earliest genes expressed in the neuroectoderm, dividing it into anterior and posterior domains with a common border that marks the mid-hindbrain junction. Otx2 is required for development of the forebrain and midbrain, and Gbx2 for the anterior hindbrain. Furthermore, opposing interactions between Otx2 and Gbx2 play an important role in positioning the mid-hindbrain boundary, where an organizer forms that regulates midbrain and cerebellum development. We show that the expression domains of Otx2 and Gbx2 are initially established independently of each other at the early headfold stage, and then their expression rapidly becomes interdependent by the late headfold stage. As we demonstrate that the repression of Otx2 by retinoic acid is dependent on an induction of Gbx2 in the anterior brain, molecules other than retinoic acid must regulate the initial expression of Otx2 in vivo. In contrast to previous suggestions that an interaction between Otx2- and Gbx2-expressing cells may be essential for induction of mid-hindbrain organizer factors such as Fgf8, we find that Fgf8 and other essential mid-hindbrain genes are induced in a correct temporal manner in mouse embryos deficient for both Otx2 and Gbx2. However, expression of these genes is abnormally co-localized in a broad anterior region of the neuroectoderm. Finally, we find that by removing Otx2 function, development of rhombomere 3 is rescued in Gbx2–/– embryos, showing that Gbx2 plays a permissive, not instructive, role in rhombomere 3 development. Our results provide new insights into induction and maintenance of the mid-hindbrain genetic cascade by showing that a mid-hindbrain competence region is initially established independent of the division of the neuroectoderm into an anterior Otx2-positive domain and posterior Gbx2-positive domain. Furthermore, Otx2 and Gbx2 are required to suppress hindbrain and midbrain development, respectively, and thus allow establishment of the normal spatial domains of Fgf8 and other genes.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

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