Epigenetic regulation of dendritic cell differentiation and function by oxidized phospholipids

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5481-5489 ◽  
Author(s):  
Stephan Blüml ◽  
Gordin Zupkovitz ◽  
Stefanie Kirchberger ◽  
Maria Seyerl ◽  
Valery N. Bochkov ◽  
...  
Keyword(s):  
Adaptive Immune Response ◽  
Nuclear Factor Κb ◽  
Interleukin 12 ◽  
Oxidized Phospholipids ◽  
Toll Like Receptor ◽  
Inflammatory Reactions ◽  
Dendritic Cell Differentiation ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli ◽  
And Function

AbstractDendritic cells (DCs) are the key cell type in the regulation of an adaptive immune response. Under inflammatory conditions monocytes can give rise to immunostimulatory DCs, depending on microenvironmental stimuli. Here we show that oxidized phospholipids (Ox-Pls), which are generated during inflammatory reactions, dysregulate the differentiation of DCs. DCs generated in the presence of Ox-Pls up-regulated the typical DC marker DC-SIGN but did not express CD1a, CD1b, and CD1c. These DCs generated in the presence of Ox-Pls had a substantially diminished T cell–stimulating capacity after stimulation with Toll-like receptor ligands. Toll-like receptor ligand–induced production of interleukin-12 also was strongly diminished, whereas induction of CD83 was not altered. In addition, we found that Ox-Pls strongly inhibit inflammatory stimuli-induced phosphorylation of histone H3, a key step of interleukin-12 production, yet leaving activation of nuclear factor-κB unaltered. Taken together, Ox-Pls present during differentiation yielded DCs with a reduced capacity to become immunostimulatory mature DCs. Furthermore, the presence of Ox-Pls blocked histone modifications required for full activation of DCs. Therefore, inflammation-derived Ox-Pls control DC functions in part by epigenetic mechanisms.

scholarly journals Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes

2004 ◽  
Vol 199 (12) ◽  
pp. 1631-1640 ◽  
Author(s):  
Melissa W. Boulé ◽  
Courtney Broughton ◽  
Fabienne Mackay ◽  
Shizuo Akira ◽  
Ann Marshak-Rothstein ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Cell Activation ◽  
Critical Role ◽  
Adaptive Immune Response ◽  
Foreign Protein ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Dendritic Cell Activation

Dendritic cell (DC) activation by nucleic acid–containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcγRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.

A cell-surface molecule selectively expressed on murine natural interferon–producing cells that blocks secretion of interferon-alpha

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4201-4206 ◽  
Author(s):  
Amanda Blasius ◽  
William Vermi ◽  
Anne Krug ◽  
Fabio Facchetti ◽  
Marina Cella ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Interleukin 12 ◽  
Surface Molecule ◽  
Adaptive Responses ◽  
Cell Surface Molecule ◽  
Peripheral Tissues ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli

Abstract Natural interferon (IFN)-producing cells (IPCs) recognize certain viruses and DNA containing deoxycytidylate-phosphatedeoxyguanylate (CpG) motifs through the toll-like receptor (TLR) 9, resulting in secretion of IFN-α, interleukin 12 (IL-12), and proinflammatory chemokines. Human IPCs are found mainly in inflamed lymph nodes, where they are presumably recruited from the blood to activate both innate and adaptive responses to microbial infections. Demonstrating IPC recruitment and function in murine infection models has been difficult because multiple antibodies are required to distinguish IPCs from other immune cells and very few IPCs can be recovered from lymph nodes. Here we describe a monoclonal antibody (mAb) that exclusively detects murine IPCs in all lymphoid organs under both normal and inflammatory conditions. Using this antibody, we demonstrate that IPCs are normally present in the T-cell zone of lymph nodes and spleen and that inoculation of peripheral tissues with inflammatory stimuli triggers recruitment of IPC into sentinel lymph nodes, whether the stimuli are able to directly stimulate IPCs through TLR or not. Remarkably, we show that incubation of IPCs with the antibody in vitro or administration of the antibody in vivo dramatically reduce secretion of IFN-α in response to CpG DNA without causing IPC depletion. Thus, the antibody identifies an IPC-specific surface molecule that, when engaged, inhibits IFN-α secretion. (Blood. 2004;103:4201-4206)

Dendritic Cells as Arbiters of Peritoneal Immune Responses

2006 ◽  
Vol 26 (1) ◽  
pp. 8-25 ◽  
Author(s):  
Michelle L. McCully ◽  
Joaquín Madrenas
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Immune Defense ◽  
Dendritic Cell Differentiation ◽  
Adaptive Immune ◽  
The Past ◽  
Key Players ◽  
And Function

During the past few years, there has been a substantial increase in the understanding of innate immunity. Dendritic cells are emerging as key players in the orchestration of this early phase of immune responses, with a role that will translate into the subsequent type of adaptive immune response against infection. Here we provide an overview of dendritic cell differentiation and function, with particular emphasis on those features unique to the immune defense of the peritoneal cavity and in the context of peritoneal dialysis-associated immune responses. The reader is referred to the primary references included in the accompanying list for specific details in this fascinating field.

scholarly journals MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1α

2004 ◽  
Vol 200 (5) ◽  
pp. 601-611 ◽  
Author(s):  
Nobuaki Sato ◽  
Naoyuki Takahashi ◽  
Koji Suda ◽  
Midori Nakamura ◽  
Mariko Yamaki ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Adaptor Molecule ◽  
Receptor Activator ◽  
And Function ◽  
Myeloid Differentiation Factor ◽  
Receptor Domain ◽  
Receptor Family

Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll–IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88−/−) mice and TRIF-deficient (TRIF−/−) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1α stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF−/− mice, but not MyD88−/− mice. These factors stimulated receptor activator of nuclear factor-κB ligand mRNA expression in TRIF−/− osteoblasts, but not MyD88−/− osteoblasts. LPS stimulated IL-6 production in TRIF−/− osteoblasts, but not TRIF−/− macrophages. LPS and IL-1α enhanced the survival of TRIF−/− osteoclasts, but not MyD88−/− osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MyD88−/− mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover.

IKKα in the regulation of inflammation and adaptive immunity

2007 ◽  
Vol 35 (2) ◽  
pp. 270-272 ◽  
Author(s):  
T. Lawrence ◽  
M. Bebien
Keyword(s):  
Adaptive Immunity ◽  
Adaptive Immune Response ◽  
Nuclear Factor Κb ◽  
Catalytic Subunits ◽  
Adaptive Immune ◽  
Inflammatory Stimuli ◽  
Important Regulator ◽  
Beneficial Response ◽  
Antigen Presenting ◽  
Inflammatory Signalling

Inflammation is a beneficial response to insult or injury which plays an important role in orchestrating the adaptive immune response. The resolution of acute inflammation is an active process that involves the release of anti-inflammatory mediators and the termination of pro-inflammatory signalling pathways coincident with leucocyte apoptosis and phagocytic clearance and the migration of antigen-presenting cells from the site of inflammation to the local lymphatic tissue. The latter process is required for the development of adaptive immunity and immunological memory. The NF-κB (nuclear factor κB) pathway is an important regulator of inflammation and immunity; NF-κB activation is controlled by IKK [IκB (inhibitor of NF-κB) kinase] complex, which regulates NF-κB activation in response to pro-inflammatory stimuli. The IKK complex has two catalytic subunits, IKKα and IKKβ; recent research shows that these highly homologous kinases have distinct roles in inflammation and adaptive immunity. Here, we discuss the emerging roles for IKKα in the tight regulation of inflammation and the development of adaptive immune responses.

scholarly journals A type I interferon autocrine–paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells

2005 ◽  
Vol 201 (9) ◽  
pp. 1435-1446 ◽  
Author(s):  
Grégory Gautier ◽  
Martine Humbert ◽  
Florence Deauvieau ◽  
Mathieu Scuiller ◽  
John Hiscott ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nuclear Factor Κb ◽  
Poly I:C ◽  
Interleukin 12 ◽  
Mouse Bone Marrow ◽  
Type I ◽  
Type I Ifn ◽  
Toll Like Receptor ◽  
Mrna Accumulation ◽  
Dependent Pathway

Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-κB (NF-κB)–dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-β mRNA accumulation by mouse bone marrow–derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1−/− and IFNAR−/− mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-β mRNA accumulation were strongly inhibited in IFNAR−/− BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-λ1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-κB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.

Tanshinone IIA attenuates elastase-induced AAA in rats via inhibition of MyD88-dependent TLR-4 signaling

VASA ◽  
2014 ◽  
Vol 43 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Tao Shang ◽  
Feng Ran ◽  
Qian Qiao ◽  
Zhao Liu ◽  
Chang-Jian Liu
Keyword(s):  
Nuclear Factor Κb ◽  
Tanshinone Iia ◽  
Myeloid Differentiation ◽  
Aortic Tissue ◽  
Toll Like Receptor ◽  
Sprague Dawley ◽  
Toll Like Receptor 4 ◽  
Tissue Samples ◽  
Myeloid Differentiation Factor ◽  
And Control

Background: The purpose of this study was to determine whether myeloid differentiation factor88-dependent Toll-Like Receptor-4 (TLR-4) signaling contributed to the inhibition of abdominal aortic aneurysm (AAA) by Tanshinone IIA (Tan IIA). Materials and methods: Male Sprague-Dawley rats (n = 12 / group) were randomly distributed into three groups: Tan IIA, control, and sham. The rats from Tan IIA and control groups under-went intra-aortic elastase perfusion to induce AAAs, and those in the sham group were perfused with saline. Only the Tan IIA group received Tan IIA (2 mg / rat / d). Aortic tissue samples were harvested at 24 d after perfusion and evaluated using reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence. Results: The over-expression of Toll-Like Receptor-4 (TLR-4), Myeloid Differentiation factor 88 (MyD88), Phosphorylated Nuclear Factor κB (pNF-κB) and Phosphorylated IκBα (pIκBα) induced by elastase perfusion were significantly decreased by Tan IIA treatment. Conclusions: Tan IIA attenuates elastase-induced AAA in rats possibly via the inhibition of MyD88-dependent TLR-4 signaling, which may be one potential explanation of why Tan IIA inhibits AAA development through multiple effects.

scholarly journals Mannoproteins from Cryptococcus neoformans Promote Dendritic Cell Maturation and Activation

2005 ◽  
Vol 73 (2) ◽  
pp. 820-827 ◽  
Author(s):  
Donatella Pietrella ◽  
Cristina Corbucci ◽  
Stefano Perito ◽  
Giovanni Bistoni ◽  
Anna Vecchiarelli
Keyword(s):  
Cryptococcus Neoformans ◽  
Nuclear Factor Κb ◽  
Dendritic Cell Maturation ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Histocompatibility Complex ◽  
Factor Alpha ◽  
Human Dendritic Cells ◽  
Mannose Receptors

ABSTRACT Our previous data show that mannoproteins (MPs) from Cryptococcus neoformans are able to induce protective responses against both C. neoformans and Candida albicans. Here we provide evidence that MPs foster maturation and activation of human dendritic cells (DCs). Maturation was evaluated by the ability of MPs to facilitate expression of costimulatory molecules such as CD40, CD86, CD83, and major histocompatibility complex classes I and II and to inhibit receptors such as CD14, CD16, and CD32. Activation of DCs was measured by the capacity of MPs to promote interleukin-12 and tumor necrosis factor alpha secretion. DC-induced maturation and interleukin-12 induction are largely mediated by engagement of mannose receptors and presume MP internalization and degradation. DC activation leads to IκBα phosphorylation, which is necessary for nuclear factor κB transmigration into the nucleus. MP-loaded DCs are efficient stimulators of T cells and show a remarkable capacity to promote CD4 and CD8 proliferation. In conclusion, we have evidenced a novel regulatory role of MPs that promotes their candidacy as a vaccine against fungi.

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