scholarly journals Small Molecule Inhibitors Targeting Nuclear Factor κB Activation Markedly Reduce Expression of Interleukin-2, but Not Interferon-γ, Induced by Phorbol Esters and Calcium Ionophores

2021 ◽  
Vol 22 (23) ◽  
pp. 13098
Author(s):  
Yumiko Tanaka ◽  
Ayaka Nakao ◽  
Yasunobu Miyake ◽  
Yukina Higashi ◽  
Riho Tanigaki ◽  
...  
Keyword(s):  
T Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Effector T Cells ◽  
Nuclear Factor ◽  
Ifn Γ ◽  
Primary Effector ◽  
Mouse Lymphoma

The T-box transcription factor Eomesodermin (Eomes) promotes the expression of interferon-γ (IFN-γ). We recently reported that the small molecule inhibitors, TPCA-1 and IKK-16, which target nuclear factor κB (NF-κB) activation, moderately reduced Eomes-dependent IFN-γ expression in mouse lymphoma BW5147 cells stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM). In the present study, we investigated the direct effects of NF-κB on IFN-γ expression in mouse lymphoma EL4 cells and primary effector T cells. Eomes strongly promoted IFN-γ expression and the binding of RelA and NFATc2 to the IFN-γ promoter when EL4 cells were stimulated with PMA and IM. Neither TPCA-1 nor IKK-16 reduced IFN-γ expression; however, they markedly decreased interleukin (IL)-2 expression in Eomes-transfected EL4 cells. Moreover, TPCA-1 markedly inhibited the binding of RelA, but not that of Eomes or NFATc2 to the IFN-γ promoter. In effector CD4+ and CD8+ T cells activated with anti-CD3 and anti-CD28 antibodies, IFN-γ expression induced by PMA and A23187 was not markedly decreased by TPCA-1 or IKK-16 under conditions where IL-2 expression was markedly reduced. Therefore, the present results revealed that NF-κB is dispensable for IFN-γ expression induced by PMA and calcium ionophores in EL4 cells expressing Eomes and primary effector T cells.

Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4615-4621 ◽  
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Roberto Sala ◽  
Matteo Moroni ◽  
Mirca Lazzaretti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Lymphocytes ◽  
Bone Disease ◽  
Nuclear Factor Κb ◽  
Myeloma Cell ◽  
Nuclear Factor ◽  
Free System ◽  
Receptor Activator ◽  
Ifn Γ

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-κB ligand (RANKL), and interferon γ (IFN-γ) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti–interleukin 6 (anti–IL-6) or anti–IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-γ by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell–free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 μg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand with a Superior Therapeutic Index

2020 ◽  
Vol 63 (20) ◽  
pp. 12043-12059
Author(s):  
Vagelis Rinotas ◽  
Athanasios Papakyriakou ◽  
Foteini Violitzi ◽  
Christos Papaneophytou ◽  
Maria-Dimitra Ouzouni ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Index ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Receptor Activator

scholarly journals Interleukin 12 Protects from a T Helper Type 1–mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon γ, Nitric Oxide, and Apoptosis

1999 ◽  
Vol 189 (2) ◽  
pp. 219-230 ◽  
Author(s):  
Teresa K. Tarrant ◽  
Phyllis B. Silver ◽  
Jennifer L. Wahlsten ◽  
Luiz V. Rizzo ◽  
Chi-Chao Chan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Interferon Γ ◽  
Effector T Cells ◽  
T Helper ◽  
Experimental Autoimmune Uveitis ◽  
Ifn Γ ◽  
Helper Type ◽  
Experimental Autoimmune

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon γ (IFN-γ) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-γ production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-γ–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-γ, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

scholarly journals Double-Stranded RNA Cooperates with Interferon-γ and IL-1β to Induce Both Chemokine Expression and Nuclear Factor-κB-Dependent Apoptosis in Pancreatic β-Cells: Potential Mechanisms for Viral-Induced Insulitis and β-Cell Death in Type 1 Diabetes Mellitus

Endocrinology ◽  
2002 ◽  
Vol 143 (4) ◽  
pp. 1225-1234 ◽  
Author(s):  
Dongbo Liu ◽  
Alessandra K. Cardozo ◽  
Martine I. Darville ◽  
Décio L. Eizirik
Keyword(s):  
Promoter Activity ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Double Stranded Rna ◽  
Ifn Γ

Abstract Viral infections may trigger the autoimmune assault leading to type 1 diabetes mellitus. Double-stranded RNA (dsRNA) is produced by many viruses during their replicative cycle. The dsRNA, tested as synthetic poly(IC) (PIC), in synergism with the proinflammatory cytokines interferon-γ (IFN-γ) and/or IL-1β, results in nitric oxide production, Fas expression, β-cell dysfunction, and death. Activation of the transcription nuclear factor-κB (NF-κB) is required for PIC-induced inducible nitric oxide synthase expression in β-cells, and we hypothesized that this transcription factor may also participate in PIC-induced Fas expression and β-cell apoptosis. This hypothesis, and the possibility that PIC induces expression of additional chemokines and cytokines (previously reported as NF-κB dependent) in pancreatic β-cells, was investigated in the present study. We observed that the PIC-responsive region in the Fas promoter is located between nucleotides −223 and −54. Site-directed mutations at the NF-κB and CCAAT/enhancer binding protein-binding sites prevented PIC-induced Fas promoter activity. Increased Fas promoter activity was paralleled by enhanced susceptibility of PIC + cytokine-treated β-cells to apoptosis induced by Fas ligand. β-Cell infection with the NF-κB inhibitor AdIκB(SA)2 prevented both necrosis and apoptosis induced by PIC + IL-1β or PIC + IFN-γ. Messenger RNAs for several chemokines and one cytokine were induced by PIC, alone or in combination with IFN-γ, in pancreatic β-cells. These included IP-10, interferon-γ-inducible protein-10, IL-15, macrophage chemoattractant protein-1, fractalkine, and macrophage inflammatory protein-3α. There was not, however, induction of IL-1β expression. We propose that dsRNA, generated during a viral infection, may contribute for β-cell demise by both inducing expression of chemokines and IL-15, putative contributors for the build-up of insulitis, and by synergizing with locally produced cytokines to induce β-cell apoptosis. Activation of the transcription factor NF-κB plays a central role in at least part of the deleterious effects of dsRNA in pancreatic β-cells.

Regulation of interferon-γ gene expression by nuclear factor of activated T cells

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1480-1488 ◽  
Author(s):  
Alexander Kiani ◽  
Francisco J. Garcı́a-Cózar ◽  
Ivonne Habermann ◽  
Stefanie Laforsch ◽  
Toni Aebischer ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
T Cell Clone ◽  
Ifn Γ

Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-α. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- γ (IFN-γ) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-γ production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4–independent defect in expression of IFN-γ mRNA and protein. Reduced IFN-γ production by NFAT1−/−× IL-4−/− T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1−/−× IL-4−/− mice show increased susceptibility to infection with the intracellular parasiteLeishmania major. Moreover, IFN-γ production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-γ production by T cells is regulated by NFAT1, most likely at the level of gene transcription.

CD4+CD25- effector T cells from healthy controls and MS patients do not differ in mRNA expression of IFN-γ, IL-2, and TNF-α

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
A Hug ◽  
J Haas ◽  
A Viehöver ◽  
B Fritz ◽  
B Storch-Hagenlocher ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Effector T Cells ◽  
Healthy Controls ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052098094
Author(s):  
Shuang Qin ◽  
Li Li ◽  
Jia Liu ◽  
Jinrui Zhang ◽  
Qing Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Unexplained Recurrent Spontaneous Abortion ◽  
Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

scholarly journals THU0052 RELATIONSHIP BETWEEN INTERFERON-Γ-PRODUCING IMMUNOCOMPETENT CELLS AND DISEASE ACTIVITY IN ADULT-ONSET STILL’S DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 238.1-238
Author(s):  
Y. Shimojima ◽  
D. Kishida ◽  
T. Ichikawa ◽  
Y. Sekijima
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
Nk Cells ◽  
Acute Phase ◽  
Serum Ferritin ◽  
Interferon Γ ◽  
Adult Onset Still’S Disease ◽  
Still’S Disease ◽  
Ifn Γ ◽  
Adult Onset Still's Disease

Background:In the acute phase of adult-onset Still’s disease (AOSD), elevated levels of proinflammatory cytokines including interferon-γ (IFN-γ) are shown. Moreover, IFN-γ impacts on activating macrophages which play a crucial role in the pathogenesis of AOSD. Natural killer (NK) cells and T helper cells are in charge of secreting IFN-γ in the innate and adaptive immune systems of disease, respectively. However, the features of their IFN-γ-producing variation depending on disease activity are still uncertain in AOSD.Objectives:We investigated characteristics of IFN-γ-producing CD4+T cells and NK cells in patients with AOSD.Methods:Twenty-four patients in the acute phase of AOSD (active AOSD), 8 of them after treatment (remission), and 12 healthy controls (HC) were recruited in this study. Peripheral blood mononuclear cells and serum samples were provided from them for the experimental analysis. Flow cytometry was used for analyzing CD4+T cells, CD4+regulatory T cells (Tregs), NK cells, and their intracellular IFN-γ expression levels as well as suppression assay of Tregs. The serum concentration of interleukin-18 (IL-18) was measured using commercially available ELISA kit. Relationship between the analyzed data and clinical findings related to disease activity were statistically evaluated.Results:IFN-γ expression in CD4+T cells was significantly higher in active AOSD than in HC (p < 0.05). Tregs also significantly indicated higher expression of IFN-γ in active AOSD than in HC (p < 0.0001); and moreover, Tregs were significantly impaired in their suppression ability (p < 0.05). In both CD4+T cells and Tregs, expression of IFN-γ was significantly correlated with serum ferritin levels in active AOSD (p < 0.05). IFN-γ expression in CD4+T cells was significantly higher in patients with splenomegaly than those without that (p < 0.05). The proportion of NK cells was significantly lower in active AOSD than in HC (p < 0.005), whereas IFN-γ expression in NK cells was significantly higher in active AOSD than in HC (p < 0.0005). The number of NK cells and IFN-γ-expressing NK cells had inverse relationship with serum ferritin levels in active AOSD (p < 0.05 and p < 0.005, respectively). Increased number of NK cells and their decreased expression of IFN-γ were significantly demonstrated in remission (p < 0.05). In the analyses of NK cell subsets, lower expression of IFN-γ in CD56brightNK cells and higher that in CD56dimNK cells were significantly indicated in active AOSD than HC (p < 0.05). In remission, IFN-γ expression was significantly decreased in CD56dimNK cells (p < 0.05) despite no significant recovery of that in CD56brightNK cells (p = 0.311). Meanwhile, increased expression of IFN-γ in CD56brightNK cells was demonstrated in only patients who were treated with biologics. Although serum levels of IL-18 were significantly higher in active AOSD than in remission and HC; however, they had no significant correlations with any analyzed data.Conclusion:CD4+T cells and NK cells promote IFN-γ expression in the acute phase of AOSD. Meanwhile, increased expression of IFN-γ in CD4+T cells and decreased number of NK cells were correlated with serum ferritin levels, suggesting that they are indicators of disease activity. Furthermore, high disease activity may impact on the alteration of IFN-γ-producing balance in two distinct population of NK cells, and the plasticity of Tregs leading to defect in suppression ability.Disclosure of Interests:None declared

scholarly journals (–)-Loliolide Isolated from Sargassum horneri Suppressed Oxidative Stress and Inflammation by Activating Nrf2/HO-1 Signaling in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 856
Author(s):  
Eui-Jeong Han ◽  
Ilekuttige Priyan Shanura Fernando ◽  
Hyun-Soo Kim ◽  
Dae-Sung Lee ◽  
Areum Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Factor Κb ◽  
Sargassum Horneri ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Hacat Keratinocytes ◽  
Tnf Α ◽  
Ifn Γ

The present study evaluated the effects of (–)-loliolide isolated from Sargassum horneri (S. horneri) against oxidative stress and inflammation, and its biological mechanism in interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocytes. The results showed that (–)-loliolide improved the cell viability by reducing the production of intracellular reactive oxygen species (ROS) in IFN-γ/TNF-α-stimulated HaCaT keratinocytes. In addition, (–)-loliolide effectively decreased the expression of inflammatory cytokines (interleukin (IL)-4 IL-6, IL-13, IFN-γ and TNF-α) and chemokines (CCL11 (Eotaxin), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)), by downregulating the expression of epidermal-derived initial cytokines (IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)). Furthermore, (–)-loliolide suppressed the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling, whereas it activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Interestingly, the cytoprotective effects of (–)-loliolide against IFN-γ/TNF-α stimulation were significantly blocked upon inhibition of HO-1. Taken together, these results suggest that (–)-loliolide effectively suppressed the oxidative stress and inflammation by activating the Nrf2/HO-1 signaling in IFN-γ/TNF-α-stimulated HaCaT keratinocytes.

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