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EBioMedicine May 2020Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In...
BACKGROUND
Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far.
METHODS
We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and T-cell priming.
FINDINGS
PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4T-cells into T1 and T2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects.
INTERPRETATION
Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions.
FUNDING
This research project was supported by the Austrian Research Promotion Agency (Vienna, Austria; grant "APOSEC" 862068; 2015-2019) and the Vienna Business Agency (Vienna, Austria; grant "APOSEC to clinic" 2343727).
Topics: Adult; Animals; Antigens, CD1; Biomarkers; CD11c Antigen; Cell Differentiation; Cell Proliferation; Culture Media, Conditioned; Dendritic Cells; Dermatitis, Contact; Dinitrofluorobenzene; Female; Gamma Rays; Gene Expression; Histocompatibility Antigens Class II; Humans; Immunologic Factors; Lipids; Lipopolysaccharides; Mice; Monocytes; Primary Cell Culture; Skin; Th1 Cells; Th2 Cells; Tissue Culture Techniques
PubMed: 32403085
DOI: 10.1016/j.ebiom.2020.102774 -
Molecules (Basel, Switzerland) Apr 2019Physcion is well known for the treatment of carcinoma. However, the therapeutic effect of physcion on atopic dermatitis (AD) through the inhibition of thymic stromal...
Physcion is well known for the treatment of carcinoma. However, the therapeutic effect of physcion on atopic dermatitis (AD) through the inhibition of thymic stromal lymphopoietin (TSLP) level remains largely unknown. In this study, we investigated the anti-AD effect of physcion using HMC-1 cells, splenocytes, and a murine model. Treatment with physcion decreased production and mRNA expression levels of TSLP, IL-6, TNF-ɑ, and IL-1β in activated HMC-1 cells. Physcion reduced the expression levels of RIP2/caspase-1 and phospho (p)ERK/pJNK/pp38 in activated HMC-1 cells. Physcion suppressed the expression levels of pIKKβ/NF-κB/pIkB in activated HMC-1 cells. Moreover, physcion attenuated the production levels of TSLP, IL-4, IL-6, TNF-, and IFN-γ from activated splenocytes. Oral administration of physcion improved the severity of 2,4-dinitrochlorobenzene-induced AD-like lesional skin through reducing infiltration of inflammatory cells and mast cells, and the protein and mRNA levels of TSLP, IL-4, and IL-6 in the lesional skin tissues. Physcion attenuated histamine, IgE, TSLP, IL-4, IL-6, and TNF- levels in serum. In addition, physcion inhibited caspase-1 activation in the lesional skin tissues. These findings indicate that physcion could ameliorate AD-like skin lesions by inhibiting TSLP levels via caspase-1/MAPKs/NF-kB signalings, which would provide experimental evidence of the therapeutic potential of physcion for AD.
Topics: Animals; Caspase 1; Cytokines; Dermatitis, Atopic; Dinitrofluorobenzene; Emodin; Histamine; Humans; MAP Kinase Signaling System; Mast Cells; Mice; NF-kappa B; Thymic Stromal Lymphopoietin
PubMed: 30991764
DOI: 10.3390/molecules24081484 -
International Journal of Molecular... Dec 2018Inflammatory bowel disease is triggered by an uncontrolled immune response associated with genetic, environmental, and intestinal microbiota imbalance. Ipomoea...
Inflammatory bowel disease is triggered by an uncontrolled immune response associated with genetic, environmental, and intestinal microbiota imbalance. Ipomoea asarifolia (IA), popularly known as "salsa" or "brave salsa", belongs to the Convolvulaceae family. The aim of this approach was to study the preventive effect of IA aqueous extract in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats. Rats pretreated with IA extract or sulfasalazine (SSZ) received intracolonic instillation of DNBS in 50% ethanol (v/v). IA extract presented a protective effect against intestinal inflammation, with improvement in the disease activity index and macroscopic damage. IA or SSZ significantly reduced myeloperoxidase activity, and also down-regulation of the gene expression of JNK1, NF-κβ-p65, STAT3, and decreased levels of TNFα, IL-1β, and increased IL-10, associated with a significant improvement of oxidative stress, in addition to a reduction in MDA and an increase of glutathione in colonic tissue. The protective effect of the extract was also confirmed in histological evaluation, showing preservation of the colonic cytoarchitecture. Immunohistochemical analysis revealed down-regulation of NF-κβ-p65, iNOS, IL-17, and up-regulation of SOCs-1 and MUC-2. IA extract presents antioxidant and anti-inflammatory intestinal properties, and proved to be a potential application for preventing damage induced by DNBS.
Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Dinitrofluorobenzene; Female; Gene Expression Regulation; Intestines; Ipomoea; Mitogen-Activated Protein Kinase 8; NF-kappa B; Organ Size; Oxidative Stress; Peroxidase; Plant Extracts; Rats, Wistar; STAT3 Transcription Factor
PubMed: 30545135
DOI: 10.3390/ijms19124016 -
The Journal of Biological Chemistry Nov 1976Cross-linking reagents have been used to link covalently adjacent subunits of solubilized spinach chloroplast coupling factor 1, which is a latent ATPase....
Cross-linking reagents have been used to link covalently adjacent subunits of solubilized spinach chloroplast coupling factor 1, which is a latent ATPase. 1,5-Difluoro-2,4-dinitrobenzene, dimethyl-3,3'-dithiobispropionimidate, and dimethylsuberimidate are able to form bridges of 3 to 11 A between amino groups, and hydrogen peroxide and the o-phenanthroline-cupric ion complex catalyze the oxidation of intrinsic sulfhydryl groups. The five individual subunit bands (alpha, beta, gamma, delta, and epsilon) and several new aggregate bands can be separated by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The same four fastest moving aggregate bands, as characterized by their mobilities, migrate more slowly than the heaviest subunit band and appear with all of the cross-linkers employed. The subunit composition of the aggregate bands has been determined through the use of the reversible cross-linkers, dimethyldithiobispropionimidate, (o-phenanthroline)2Cu(II), and H2O2, and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis in which aggregates are separated in the first dimension, the disulfide cross-links are cleaved, and the individual subunits present in the aggregates are separated in the second dimension. The subunits are detected by Coomassie brilliant blue staining and by labeling some of the sulfhydryl groups of the gamma and epsilon subunits with radioactive N-ethylmaleimide. The results obtained indicate that the alpha and beta subunits can cross-link directly with each of the other subunits, that two beta subunits are adjacent, and that gamma epsilon, gamma epsilon 2, alpha delta, and beta delta aggregates are present. A minimal subunit stoichiometry consistent with these results is alpha 2 beta 2 gamma delta epsilon 2. A possible structural model of the coupling factor is derived from the data. Similar, but less extensive, experiments have been carried out with the heat-activated coupling factor (which is an ATPase); no differences in the spatial arrangement of subunits are detected from the two-dimensional gel electrophoresis analysis of the cross-linked aggregates.
Topics: Adenosine Triphosphatases; Chloroplasts; Dinitrofluorobenzene; Ethylmaleimide; Macromolecular Substances; Molecular Weight; Plant Proteins; Plants; Protein Binding; Protein Conformation; Spectrometry, Fluorescence
PubMed: 136444
DOI: No ID Found -
Scandinavian Journal of Immunology Apr 2015Of the biogenic polyamines, spermidine is a natural constituent of living cells and organisms. Spermidine is associated with regulation of cell growth, proliferation and...
Of the biogenic polyamines, spermidine is a natural constituent of living cells and organisms. Spermidine is associated with regulation of cell growth, proliferation and differentiation, and with the suppression of oxidation and inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that has a complex and multiple pathogenesis, which includes genetic abnormality, modified or abnormal immune response and the production of nitric oxide and reactive oxygen species. We investigated whether spermidine can relieve AD-like clinical manifestation induced by the continual application of 2,4-dinitrofluorobenzene (DNFB) in NC/Nga mice. Spermidine at concentrations of 1 or 10 mg/kg reduced increasing ear swelling and attenuated oedema, haemorrhage and hyperkeratosis in AD-like skin lesions. Repetitive application of DNFB induced inflammatory cell infiltration to skin lesions, whereas intraperitoneal injection of spermidine inhibited DNFB-evoked infiltration of eosinophils, mast cells and T lymphocytes. Furthermore, spermidine suppressed mast cell degranulation and production of interferon-gamma by activated CD4(+) T cells in AD-like skin lesions. Spermidine may be a potential therapeutic agent for treatment of AD.
Topics: Animals; CD4-Positive T-Lymphocytes; Dermatitis, Atopic; Dinitrofluorobenzene; Histocytochemistry; Immunoglobulin E; Interferon-gamma; Interleukin-4; Male; Mice; Random Allocation; Specific Pathogen-Free Organisms; Spermidine
PubMed: 25645543
DOI: 10.1111/sji.12274 -
Redox Biology Jun 2018Low molecular weight reactive chemicals causing skin and respiratory allergies are known to activate dendritic cells (DC), an event considered to be a key step in both...
Low molecular weight reactive chemicals causing skin and respiratory allergies are known to activate dendritic cells (DC), an event considered to be a key step in both pathologies. Although generation of reactive oxygen species (ROS) is considered a major danger signal responsible for DC maturation, the mechanisms leading to cellular redox imbalance remain poorly understood. Therefore, the aim of this study was to unveil the origin and kinetics of redox imbalance elicited by 1-fluoro-2,4-dinitrobenzene (DNFB) and trimellitic anhydride chloride (TMAC), two golden standards of skin and chemical respiratory allergy, respectively. To track this goal, we addressed the time course modifications of ROS production and cellular antioxidant defenses as well as the modulation of MAPKs signaling pathways and transcription of pathophysiological relevant genes in THP-1 cells. Our data shows that the thiol-reactive sensitizer DNFB directly reacts with cytoplasmic glutathione (GSH) causing its rapid and marked depletion which results in a general increase in ROS accumulation. In turn, TMAC, which preferentially reacts with amine groups, induces a delayed GSH depletion as a consequence of increased mitochondrial ROS production. These divergences in ROS production seem to be correlated with the different extension of intracellular signaling pathways activation and, by consequence, with distinct transcription kinetics of genes such as HMOX1, IL8, IL1B and CD86. Ultimately, our observations may help explain the distinct DC phenotype and T-cell polarizing profile triggered by skin and respiratory sensitizers.
Topics: Anhydrides; Antioxidants; Cell Line; Dendritic Cells; Dinitrofluorobenzene; Glutathione; Heme Oxygenase-1; Humans; Kinetics; Mitogen-Activated Protein Kinase Kinases; Monocytes; Oxidation-Reduction; Reactive Oxygen Species; Skin
PubMed: 29477863
DOI: 10.1016/j.redox.2018.02.002 -
Molecules (Basel, Switzerland) Apr 2023Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic...
Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic formulations. RSV-GS is a synthetic hydrophilic sulfated glycosylated derivative inspired by marine natural products that present a lower cytotoxicity than RSV while exhibiting similar levels of bioactivity. Herein, we predict the skin sensitization potential of this new compound using an in vitro approach based on the OECD 442E guideline. Furthermore, the anti-allergic potential of RSV-GS was also disclosed. The monocyte THP-1 cell line was stimulated with RSV and RSV-GS in the presence or absence of the extreme skin allergen 1-fluoro-2,4-dinitrobenzene (DNFB). The results demonstrated that RSV-GS alone (500 µM) evoked a relative fluorescence index (RFI) lower than the thresholds established by the OECD guideline for CD54 (200%) and CD86 (150%), indicating the absence of a skin sensitization potential. Interestingly, in the presence of the skin allergen DNFB, RSV-GS exhibited the ability to rescue the DNFB-induced maturation of THP-1 cells, with RFI values lower than those for RSV, suggesting the potential of RSV-GS to mitigate skin sensitization evoked by allergens and, consequently, allergic contact dermatitis. These results open new avenues for the use of RSV-GS as a safe and anti-allergic active cosmetic ingredient.
Topics: Resveratrol; Anti-Allergic Agents; Sulfates; Dinitrofluorobenzene; Allergens
PubMed: 37049922
DOI: 10.3390/molecules28073158 -
The Journal of Experimental Medicine Dec 1979Previous studies have shown that suppression of 2,4-dinitrofluorobenzene (DNFB) contact sensitivity by soluble suppressor factor (SSF) requires that the donor of immune...
Soluble factors in tolerance and contact sensitivity to 2,4-dinitrofluorobenzene in mice. III. Histocompatibility antigens associated with the hapten dinitrophenol serve as target molecules on 2,4-dinitrofluorobenzene-immune T cells for soluble suppressor factor.
Previous studies have shown that suppression of 2,4-dinitrofluorobenzene (DNFB) contact sensitivity by soluble suppressor factor (SSF) requires that the donor of immune lymph node (LN) cells and of SSF share either the H-2K and/or H-2D region of the major histocompatibility complex. Thus, target or acceptor molecules for SSF appear to be coded for by genes within the H-2K and H-2D loci. Experiments were done to investigate the nature of these target molecules and to determine what cell types expressed them. It was found that purified lymph node T cells are suppressed by SSF indicating that T cells express the acceptor molecules. Adsorption experiments showed that the only cells capable of adsorbing the suppressor factor are DNFB-immune T cells from donors which share with the factor-producing strain either the H-2K or H-2D locus. This adsorption can be specifically blocked by pretreating the immune LN cells with antibodies directed against H-2K and/or H-2D determinants or against the hapten DNP but not by antibodies against Ia or theta-antigens. Collectively, these results indicate that the target molecules are expressed only by DNFB-immune T cells and are comprised of histocompatibility antigens associated with DNP.
Topics: Animals; Antigen-Antibody Reactions; Cyclophosphamide; Dinitrofluorobenzene; H-2 Antigens; Immune Tolerance; Isoantibodies; Major Histocompatibility Complex; Mice; Mice, Inbred Strains; Nitrobenzenes; T-Lymphocytes
PubMed: 315993
DOI: 10.1084/jem.150.6.1432 -
Acta Pharmacologica Sinica Oct 2002To study the immune modulating effect of low dose of resveratrol.
AIM
To study the immune modulating effect of low dose of resveratrol.
METHODS
Concanavalin A (ConA) and Staphylococcus aureus Cowan (Sac) were used to induce the activation of T lymphocyte and antigen presenting cell and cytokine production. [3H]-Thymidine incorporation was used to evaluate the proliferation of lymphocyte. Cytokine production was detected by ELISA method. Dinitrofluorobenzene (DNFB) was used to induce mice delayed type hypersensitivity (DTH, delayed hypersensitivity) response and ear swelling was used as an evaluating indicator. Changes of lymphocyte subtypes were detected by flow cytometry.
RESULTS
Resveratrol (0.75-6 micromol/L) concentration-dependently promoted lymphocyte proliferation and IL-2 production induced by ConA. Sac induced IL-12 and IFN-gamma (interferon type II) production were also concentration-dependently enhanced by resveratrol, while IL-10 production was inhibited. Resveratrol (4 mg/kg, ig) promoted DTH response of mouse, which was suppressed by ethanol (16 %, w/v) consumption. Resveratrol treatment had no significant influence on lymphocyte subtypes in mice, however it could reverse the suppressive effect of ethanol both on macrophage percentage and on macrophage MHC-II molecule expression.
CONCLUSION
Low dose resveratrol enhanced cell-mediate immune response. Promoting Th1 cytokine production and influencing on macrophage function might be its mechanisms.
Topics: Adjuvants, Immunologic; Animals; Dinitrofluorobenzene; Hypersensitivity, Delayed; Immunity; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-2; Mice; Mice, Inbred BALB C; Resveratrol; Spleen; Stilbenes; T-Lymphocyte Subsets
PubMed: 12370094
DOI: No ID Found -
International Immunopharmacology Oct 2010Immunoregulatory effects of placental extract and placenta-derived factors have been demonstrated in various conditions. Accordingly, placental extract has been used as...
Immunoregulatory effects of placental extract and placenta-derived factors have been demonstrated in various conditions. Accordingly, placental extract has been used as certain types of medical intervention in Asian countries, whereas experimental evidence supporting its therapeutic effects and mechanisms has yet to be fully demonstrated. In this study, we investigate preventive and therapeutic effects of placental extract in contact hypersensitivity (CHS), a mouse model of allergic contact dermatitis. Administration of placental extract prior to the sensitization of allergic antigen (Ag) significantly inhibited the severity of CHS induced by Ag challenge. This effect was associated with reduced numbers of CD4(+) T cells in peripheral blood, decrease of tissue-infiltrating lymphocytes, and preferential production of Th2-type cytokines in Ag-challenged sites. In addition, CHS caused by repetitive challenges of allergic Ag was also prevented and treated by administration of placental extract. Finally, administration of cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide derived from placental extract, also alleviated CHS, suggesting its potential role in the effects of placental extract in CHS. Taken together, our findings demonstrated experimental evidence supporting immunoregulatory effects of placental extract in allergic skin diseases and elucidated its potential mechanisms.
Topics: Animals; Dermatitis, Contact; Dinitrofluorobenzene; Female; Humans; Immunologic Memory; Male; Mice; Mice, Inbred BALB C; Placenta; Pregnancy; Spleen; Transplants
PubMed: 20619383
DOI: 10.1016/j.intimp.2010.06.024