IL-4 synergistically enhances both IL-2– and IL-12–induced IFN-γ expression in murine NK cells

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 207-214 ◽  
Author(s):  
Jay H. Bream ◽  
Rafael E. Curiel ◽  
Cheng-Rong Yu ◽  
Charles E. Egwuagu ◽  
Michael J. Grusby ◽  
...  
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
T Helper ◽  
T Helper 1 ◽  
Ifn Γ ◽  
Cytokine Stimulation ◽  
Positive Effect

Abstract Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)–type cytokines like interferon-γ (IFN-γ). While investigating IL-4 regulation of IFN-γ expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-γ production and mRNA expression in spleen-derived, IL-2–cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2–induced IFN-γ production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN-γ expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-γ promoter that may be involved, NK cells from human IFN-γ promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-γ promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-γ expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. (Blood. 2003;102:207-214)

Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2668-2671 ◽  
Author(s):  
Raffaella Bonecchi ◽  
Silvano Sozzani ◽  
Johnny T. Stine ◽  
Walter Luini ◽  
Giovanna D’Amico ◽  
...  
Keyword(s):  
Constitutive Expression ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 1 ◽  
Chemokine Production ◽  
T Helper 2 ◽  
Ifn Γ

Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2668-2671 ◽  
Author(s):  
Raffaella Bonecchi ◽  
Silvano Sozzani ◽  
Johnny T. Stine ◽  
Walter Luini ◽  
Giovanna D’Amico ◽  
...  
Keyword(s):  
Constitutive Expression ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 1 ◽  
Chemokine Production ◽  
T Helper 2 ◽  
Ifn Γ

Abstract Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

scholarly journals Hlx homeobox transcription factor negatively regulates interferon-γ production in monokine-activated natural killer cells

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2481-2487 ◽  
Author(s):  
Brian Becknell ◽  
Tiffany L. Hughes ◽  
Aharon G. Freud ◽  
Bradley W. Blaser ◽  
Jianhua Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanisms ◽  
Interferon Γ ◽  
Tumor Surveillance ◽  
Protein Levels ◽  
Homeobox Transcription Factor ◽  
Ifn Γ

Abstract Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-γ). Although there is some knowledge about molecular mechanisms that induce IFN-γ in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-γ production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-γ. Ectopic Hlx expression decreases IFN-γ synthesis in primary human NK cells and IFN-γ promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-γ transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-γ, in part through the targeted depletion of STAT4.

scholarly journals T Helper Cell Type 1–associated and Cytotoxic T Lymphocyte–mediated Tumor Immunity Is Impaired in Interleukin 4–deficient Mice

1999 ◽  
Vol 189 (5) ◽  
pp. 803-810 ◽  
Author(s):  
Thomas Schüler ◽  
Zhihai Qin ◽  
Sabrina Ibe ◽  
Nancy Noben-Trauth ◽  
Thomas Blankenstein
Keyword(s):  
Tumor Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Mammary Adenocarcinoma ◽  
Interleukin 4 ◽  
T Helper ◽  
T Helper 1 ◽  
Developmental Defects ◽  
Effector Cells ◽  
Helper Cell Type ◽  
Ifn Γ

It is widely accepted that cellular immune responses are induced by CD4+ T helper 1 (Th1) cells secreting interleukin (IL)-2 and interferon (IFN)-γ. Tumor immunity is often mediated by cytotoxic T lymphocytes (CTLs) whose activation is supported by Th1 cytokines. Since IL-4 directs Th2 development and has been shown to inhibit Th1-dominated responses, we assumed that IL-4–deficient (IL-4−/−) mice would develop vigorous CTL-mediated tumor immunity compared with IL-4–competent (IL-4+/+) mice. Surprisingly, IL-4−/− mice were severely impaired to develop tumor immunity to both a mammary adenocarcinoma line and a colon carcinoma line. The lack of tumor immunity in IL-4−/− mice was associated with reduced IFN-γ production, diminished levels of tumor-reactive serum IgG2a, and undetectable CTL activity, indicating a defective Th1 response in the absence of endogenous IL-4. Anti–IL-4 monoclonal antibody blocked tumor immunity in IL-4+/+ mice when administered at the time of immunization but not at the time of challenge. Additionally, tumor immunity could be induced in IL-4−/− mice, if IL-4 was provided by gene-modified cells together with immunizing tumor cells. These results demonstrate that tumor immunity requires IL-4 in the priming phase for the generation of effector cells rather than for their maintenance and exclude secondary, developmental defects in the “knockout” strain. Together, our results demonstrate a novel and previously unanticipated role of IL-4 for the generation of Th1-associated, CTL-mediated tumor immunity.

scholarly journals Killer-Cell Inhibitory Receptors, CD158a/b, are Upregulated by Interleukin-2, but not Interferon-γ or Interleukin-4

1999 ◽  
Vol 8 (6) ◽  
pp. 313-318 ◽  
Author(s):  
Toshiaki Kogure ◽  
Hiroshi Fujinaga ◽  
Atsushi Niizawa ◽  
Le Xuan Hai ◽  
Yutaka Shimada ◽  
...  
Keyword(s):  
Nk Cells ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Target Cells ◽  
Inhibitory Receptors ◽  
Regulation Of Expression ◽  
Killer Activity ◽  
Ifn Γ

Although it is now accepted that killer-cell inhibitory receptors (KIRs), which were molecularly cloned in 1995, deliver negative signals to natural killer (NK) cells regarding the recognition of target cells, it is still unclear how the expression of these receptors on lymphocytes is regulated. Therefore, we investigated the regulation of expression of representative KIRs, CD158a and CD158b, by cytokines such as interleukin-2 (IL-2), IL-4 and interferon-γ (IFN-γ). Neither IL-4 nor IFN-γ affected the expression of CD158a/b, but incubation for 48 h with IL-2, which enhances the killer activity of NK cells, upregulated the expression of the KIRs. This upregulation by IL-2 was also observed in CD16-positive cells sorted from total lymphocytes. In contrast, IL-4, which is a downregulator of IL-2-induced killer responses, did not change the level of CD158a/b expression when added after the IL-2 treatment. These findings suggest that IL-2 plays an important role in the regulation of CD158a/b expression, and might be involved in controlling NK activity via regulating expression of these molecules.

Dendritic Cells Matured with a TLR7/8 Agonist Induce T Helper 1 Cell Polarization, Activate NK Cells and Are Thus Highly Suitable for Application in Cancer Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 358-358
Author(s):  
Felix S Lichtenegger ◽  
Katharina Mueller ◽  
Wolfgang Hiddemann ◽  
Dolores J Schendel ◽  
Marion Subklewe
Keyword(s):  
Nk Cells ◽  
T Helper Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Helper Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Low Levels

Abstract Abstract 358FN2 Dendritic cells (DCs) are important regulators of the human immune response. By means of direct intercellular interactions and secretion of cytokines, they can induce a stimulatory or a regulatory response, depending on the environment in which they developed. In vitro, it is possible to imitate this process by addition of various cytokines. The aim of this study was to evaluate DCs matured by different cytokine cocktails for expression of immunostimulatory and -inhibitory molecules and correspondent activation of T helper 1 (Th1) and natural killer (NK) cells. The selection of these cocktails was guided by potential clinical application and usage in a GMP setting. We compared three different ways of DC generation from peripheral blood monocytes of healthy donors: 1) maturation by a cocktail including the TLR7/8 agonist R848 (TLR-mDCs), 2) DC generation by the standard combination of proinflammatory cytokines (IL-4, GM-CSF, IL-1β, PGE2, TNF-α, and IL-6) applied in many clinical studies so far (cc-mDCs), and 3) addition of IL-10 in order to induce a more regulatory phenotype (IL10-mDCs). The expression of a broad range of costimulatory and coinhibitory molecules (CD80, CD86, CD273, CD274, CD275, CD276, B7-H4, HVEM, CD30L, CD70, CD134L = OX40L, CD137L = 4-1BBL) on the surface of these DC populations was analyzed by FACS. Secretion of various cytokines crucial for interaction with other immune cells (IL-12p70, IL-10, TNF-α, IFN-γ, IL-2, and TGF-β) was measured by cytometric bead array after stimulation with CD40 ligand. In order to assess the functional importance of these signals, we performed in vitro polarization assays for T helper cells after co-culture with DCs and measured the in vitro stimulatory potential of the DCs for natural killer (NK) cells by CD69 upregulation and intracellular IFN-γ staining. We could show that TLR-mDCs were characterized by a predominance of costimulatory (e.g. CD80, CD86) relative to coinhibitory molecules (e.g. CD273, CD274, HVEM). When stimulated by CD40L, they displayed a cytokine profile with very high IL-12p70 and TNF-α, but little if any IL-10 production. In a co-culture with autologous T cells, the combination of these signals resulted in a strong polarization toward IFN-γ secreting Th1 cells, with little or no stimulation of Th2 and Th17 cells. The costimulatory profile of cc-mDCs, in comparison, was shifted toward a lower expression of costimulatory molecules and similar or higher expression of coinhibitory molecules (ratio of CD86 to CD273 expression around 40 compared to > 60 for TLR-mDCs, p < 0.005). No IL-12p70 and low levels of IL-10 were secreted. These signals were reflected in a less pronounced type 1 polarization of T helper cells. IL10-mDCs expressed very low levels of CD80 and CD86 and displayed a coinhibitory molecule pattern similar to cc-mDCs. Additionally, they secreted the immunoregulatory molecule IL-10 in higher amounts and did not activate T helper cells at all. As IL-12p70 is an important factor for NK cell activation, only TLR-mDCs were capable of upregulating the activation marker CD69 on NK cells and inducing significant secretion of IFN-γ. Both Th1 and NK cells play an important role in tumor defense. With this set of data, we clearly showed that TLR-mDCs, in consequence of their positive costimulatory profile and their high IL-12p70 secretion, are superior with respect to type 1 polarization of T cells and activation of NK cells. They are therefore highly suitable for application in cancer immunotherapy. This DC type will be used in a phase I/II trial for postremission therapy in patients with non-favorable AML, which will start in our clinic in 2012. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evidence Inconsistent with a Negative Influence of T Helper 2 Cells on Protection Afforded by a Dominant T Helper 1 Response against Mycobacterium tuberculosis Lung Infection in Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 6436-6443 ◽  
Author(s):  
Yu-Jin Jung ◽  
Ronald LaCourse ◽  
Lynn Ryan ◽  
Robert J. North
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virulent Strain ◽  
Fold Increase ◽  
Negative Influence ◽  
Interleukin 4 ◽  
T Helper ◽  
T Helper 1 ◽  
Th2 Response ◽  
Ifn Γ ◽  
Stationary Level

ABSTRACT Mice incapable of generating an efficient Th2 response because of functional deletion of the genes for signal transducer and activation of transcription 6 (Stat6), interleukin-4 receptor alpha chain (IL-4Rα), or IL-4 plus IL-13 (IL-4/IL-13) were no more resistant than wild-type (WT) mice to airborne infection with virulent Mycobacterium tuberculosis. WT mice were able to control infection and hold it at a stationary level following 20 days of log linear M. tuberculosis growth. Likewise, infection was kept under control and was held at the same stationary level in IL-4/IL-13−/− mice but progressed to a slightly higher level in Stat6−/− and IL-4Rα−/− mice. The onset of stationary-level infection in WT mice was associated with the expression of Th1-mediated immunity, as evidenced by an approximately 100- to 1,000-fold increase in the lungs in the synthesis of mRNA for IL-12, gamma interferon (IFN-γ), and inducible nitric oxide synthase (NOS2) that was sustained for at least 100 days. IL-12 is essential for the induction of Th1 immunity, IFN-γ is a key Th1 cytokine involved in mediation of immunity, and NOS2 is an inducible enzyme of macrophages and is needed by these cells to express immunity. In response to infection, the lungs of Stat6−/− mice showed increases in synthesis of mRNA for IL-12, IFN-γ, and NOS2 similar to that seen in WT mice. In IL-4/IL-13−/− mice, however, synthesis of mRNA for IFN-γ and NOS2 reached higher levels than in WT mice. These results argue against the notion that a Th2 response is partly or wholly responsible for the inability of Th1-mediated immunity to resolve infection with a virulent strain of M. tuberculosis.

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

Abstract 425: Lycopene Modulates T Lymphocyte Function by Modulating Th1 Responses and Treg Lymphocyte Population

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Lynsey M Mills ◽  
Heather Wilson ◽  
Frank Thies
Keyword(s):  
T Lymphocyte ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
T Cell Subsets ◽  
Lymphocyte Function ◽  
T Helper ◽  
T Helper 1 ◽  
Peripheral Blood Mononuclear ◽  
Lymphocyte Activity ◽  
Ifn Γ

Increased lycopene intake might have cardiovascular benefits, potentially through anti-inflammatory mechanisms. We recently showed that lycopene can influence lymphocyte activity by modulating processes involved in early cellular activation. T lymphocytes comprise different subsets, T cytotoxic, T helper 1 (Th1), T helper 2 (Th2) and T regulatory cells (Treg). We aimed to determine whether lycopene could specifically modulate T-cell subsets function and activity. Peripheral blood mononuclear cells from 11 healthy adults were cultured for 18hr to 60h in the presence of lycopene-enriched liposomes (0-1.18μg lycopene/ml) with or without mitogens. The secretion of cytokines representative of Th1,Th2 and Treg activities were measured by ELISA (IL-2, IL-1β, IL-10, IFN-γ and TGF-β) or cytometric bead array (IL-4, IL-10, IL17 and IFN-γ). The population profile of Tc (CD3+/CD8+), Th (CD3+/CD4+), Treg (CD4+/CD25+), and the Treg subsets nTreg (CD4+/CD25+/FoxP3+) and iTreg (CD4+/CD25+/IL-10+) was determined by flow cytometry. After 18h incubation, IL-2 concentration in the medium was significantly reduced (-29%, p=0.001) in the presence of lycopene (1.18μg/mL). Similar effects were observed after 36h and 60h culture for IFN-γ (-23%, p=0.015), Il-10 (-30%, p=0.023), IL-17 (-30%, p=0.019) but not IL-4 or TGF-β. The proportion of Treg cell was also significantly increased by 36% (p=0.001) in the presence of lycopene (1.18μg/mL) compared with non-treated activated cells. Furthermore, the proportions of iTreg cells were significantly increased by after incubation with lycopene while the proportion of nTreg cells decreased (-20.5 %, p=0.049). We conclude that increased lycopene intake may be beneficial against atherogenesis by modulating T lymphocyte function, particularly in relation toTh1 and Treg.

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