Potential role of MRN-100, an iron-based compound, in upregulating production of cytokine IL-10 in human dendritic cells to promote an anti-inflammatory response in vitro

The hydroferrate fluid MRN-100, an iron-based compound with potent antioxidant characteristics, was examined to identify its possible anti-inflammatory effects on human dendritic cells (DCs) in vitro. Human monocyte–derived DCs were treated with MRN-100 at two concentrations (50 and 100 μL/mL) for 24 h and then stimulated with or without lipopolysaccharides (LPS). The expression of DC maturation markers was assessed by flow cytometry and the production of cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Functional assay was performed by co-culturing MRN-100-treated and untreated DCs with allogeneic naïve CD4+ T cells and assaying the T cells’ cytokine production. Results show that treatment with MRN-100 significantly upregulated the co-stimulatory molecules CD80 and CD86 and increased human leukocyte antigen-DR (HLA-DR) though not significantly. MRN-100 treatment also significantly increased the production of the anti-inflammatory cytokine interleukin (IL)-10. On the other hand, MRN-100 significantly induced the secretion of pro-inflammatory cytokines such as IL-6 only at high concentrations. Furthermore, DCs pretreated with MRN-100 and either stimulated or not with LPS were able to prime CD4+ T cells to secrete significant amounts of IL-10 while inhibiting the secretion of pro-inflammatory cytokine tumor necrosis factor (TNF)-α. These results indicate that MRN-100 is a powerful anti-inflammatory agent that promotes the generation of an anti-inflammatory immune response in vitro. MRN-100 could be beneficial for treating patients with inflammatory diseases, including arthritis and type 1 diabetes, and its potential benefits should be examined in clinical trials.

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Extract and fractions from birch bark affect stimulation of human dendritic cells and their activation of allogeneic CD4+ T cells in vitro

Planta Medica ◽

10.1055/s-0030-1264940 ◽

2010 ◽

Vol 76 (12) ◽

Author(s):

S Omarsdottir ◽

M Sigurpalsson ◽

A Eggertsdottir ◽

J Runarsson ◽

I Hardardottir ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Birch Bark ◽

Human Dendritic Cells ◽

Stimulation Of

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Aqueous extracts from Menyanthes trifoliate and Achillea millefolium affect maturation of human dendritic cells and their activation of allogeneic CD4+ T cells in vitro

Journal of Ethnopharmacology ◽

10.1016/j.jep.2011.04.006 ◽

2011 ◽

Vol 136 (1) ◽

pp. 88-93 ◽

Cited By ~ 12

Author(s):

Gudbjorg Jonsdottir ◽

Sesselja Omarsdottir ◽

Arnor Vikingsson ◽

Ingibjorg Hardardottir ◽

Jona Freysdottir

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Achillea Millefolium ◽

Aqueous Extracts ◽

Human Dendritic Cells

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Sulphated polysaccharide from the sea cucumber Cucumaria frondosa affect maturation of human dendritic cells and their activation of allogeneic CD4(+) T cells in vitro

Bioactive Carbohydrates and Dietary Fibre ◽

10.1016/j.bcdf.2013.09.009 ◽

2013 ◽

Vol 2 (2) ◽

pp. 108-117 ◽

Cited By ~ 18

Author(s):

Varsha Kale ◽

Jona Freysdottir ◽

Berit S. Paulsen ◽

Ólafur H. Friðjónsson ◽

Guðmundur Óli Hreggviðsson ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Sea Cucumber ◽

Sulphated Polysaccharide ◽

Human Dendritic Cells ◽

Cucumaria Frondosa

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Human Dendritic Cells Stimulated via TLR7 and/or TLR8 Induce the Sequential Production of Il-10, IFN-γ, and IL-17A by Naive CD4+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.0801969 ◽

2009 ◽

Vol 182 (6) ◽

pp. 3372-3379 ◽

Cited By ~ 74

Author(s):

Vincent Lombardi ◽

Laurence Van Overtvelt ◽

Stéphane Horiot ◽

Philippe Moingeon

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Ifn Γ ◽

Human Dendritic Cells

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Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1431 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1431-1437 ◽

Cited By ~ 156

Author(s):

M Croft ◽

D D Duncan ◽

S L Swain

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 Cells ◽

Peptide Antigen ◽

Naive T Cells ◽

Naïve T Cells ◽

Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

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Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model

Journal of Investigative Medicine ◽

10.1136/jim-2020-001424 ◽

2020 ◽

Vol 69 (1) ◽

pp. 28-40 ◽

Cited By ~ 1

Author(s):

Ross Cromarty ◽

Alexander Sigal ◽

Lenine Julie Liebenberg ◽

Lyle Robert Mckinnon ◽

Salim Safurdeen Abdool Karim ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Immune Activation ◽

Cd4 T Cells ◽

Drug Targets ◽

Complex Nature ◽

Peripheral Blood Mononuclear ◽

Established Risk Factor ◽

Anti Inflammatory

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

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Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

Protein & Cell ◽

10.1007/s13238-019-00662-0 ◽

2019 ◽

Vol 11 (2) ◽

pp. 108-123

Author(s):

Dan Tong ◽

Li Zhang ◽

Fei Ning ◽

Ying Xu ◽

Xiaoyu Hu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Immune Memory ◽

Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

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Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia

Clinical Science ◽

10.1042/cs20171059 ◽

2018 ◽

Vol 132 (3) ◽

pp. 419-436 ◽

Cited By ~ 16

Author(s):

Sabrina M. Scroggins ◽

Donna A. Santillan ◽

Jenna M. Lund ◽

Jeremy A. Sandgren ◽

Lindsay K. Krotz ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Inflammatory Cytokine ◽

Maternal Plasma ◽

Hypertensive Disorder ◽

Wild Type ◽

T Helper ◽

Anti Inflammatory ◽

Immune Changes ◽

Anti Inflammatory Cytokine

The pathogenesis of preeclampsia (PreE), a hypertensive disorder of pregnancy, involves imbalanced T helper (TH) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in PreE in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of PreE in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human PreE. AVP infusion throughout gestation in mice resulted in increased pro-inflammatory interferon γ (IFNg) (TH1) in the maternal plasma. The TH17-associated cytokine interleukin (IL)-17 was elevated in the maternal plasma, amniotic fluid, and placenta following AVP infusion. Conversely, the TH2-associated anti-inflammatory cytokine IL-4 was decreased in the maternal and fetal kidneys from AVP-infused dams, while IL-10 was decreased in the maternal kidney and all fetal tissues. Collectively, these results demonstrate the sufficiency of AVP to induce the immune changes typical of PreE. We investigated if T cells can respond directly to AVP by evaluating the expression of AVP receptors (AVPRs) on mouse and human CD4+ T cells. Mouse and human T cells expressed AVPR1a, AVPR1b, and AVPR2. The expression of AVPR1a was decreased in CD4+ T cells obtained from PreE-affected women. In total, our data are consistent with a potential initiating role for AVP in the immune dysfunction typical of PreE and identifies putative signaling mechanism(s) for future investigation.

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Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618364114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1099-1104 ◽

Cited By ~ 23

Author(s):

William Bracamonte-Baran ◽

Jonathan Florentin ◽

Ying Zhou ◽

Ewa Jankowska-Gan ◽

W. John Haynes ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Extracellular Vesicle ◽

Membrane Microdomains ◽

Transplant Tolerance ◽

Split Tolerance ◽

Cross Dressing

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; “cross-dressing”) of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a “split tolerance” status in mAAQ+mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC–specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1–dependent anergy in mAAQ+hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

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