Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2011-2017 ◽  
Author(s):  
Shigeaki Hida ◽  
Masumi Tadachi ◽  
Takashi Saito ◽  
Shinsuke Taki
Keyword(s):  
Negative Control ◽  
Interleukin 4 ◽  
Th2 Polarization ◽  
Kit Gene ◽  
Th2 Development ◽  
Neutral Conditions ◽  
Th2 Differentiation

Abstract Although basophils are known to produce interleukin 4 (IL-4), the roles of these cells have been documented only in mice infected with parasites or in the effector phase of allergic inflammations. Here we show that naive mice lacking the transcription factor, interferon regulatory factor 2 (IRF-2), exhibited signal transducer and activator of transcription 6 (Stat6)–independent expansion of basophils in the periphery. IRF-2 appeared to act autonomously in the cells to negatively regulate the expansion of, but not cytokine production by, basophils. Spontaneous Th2 polarization of CD4+ T cells was observed in these mice and the genetic reduction of basophil numbers by mutating the Kit gene abolished such a polarization in vivo. We also found that both basophils and IL-4 derived from them were indeed essential for Th2 development under neutral conditions in vitro. Furthermore, neutralization of IL-3 abolished IL-4 production by basophils during Th1/Th2 differentiation cultures and subsequent Th2 development. These results indicated that basophils acted as a cellular converter to turn the neutral IL-3 into the Th2-inducing IL-4 during the initiation of Th1/Th2 differentiation. Thus, the negative regulatory role of IRF-2 on the basophil population size is critically important for preventing excess Th2 polarization and the Th1/Th2 balance in naive animals.

scholarly journals Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

2015 ◽  
Vol 112 (5) ◽  
pp. 1529-1534 ◽  
Author(s):  
Jihyung Lee ◽  
Tae Hoon Kim ◽  
Fiona Murray ◽  
Xiangli Li ◽  
Sara S. Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Adenylyl Cyclases ◽  
Th2 Polarization ◽  
Th2 Immunity ◽  
Th2 Differentiation ◽  
G Protein Coupled ◽  
Camp Formation

The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c+ cells (GnasΔCD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by GnasΔCD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.

scholarly journals Impact of GPR1 signaling on maternal high-fat feeding and placenta metabolism in mice

2019 ◽  
Vol 316 (6) ◽  
pp. E987-E997 ◽  
Author(s):  
Binbin Huang ◽  
Chen Huang ◽  
Huashan Zhao ◽  
Wen Zhu ◽  
Baobei Wang ◽  
...  
Keyword(s):  
Biological Effects ◽  
Negative Control ◽  
Feedback Mechanism ◽  
High Fat ◽  
Fatty Acid Binding ◽  
Maternal Metabolism ◽  
Phosphorylated Akt

Chemerin and G protein-coupled receptor 1 (GPR1) are increased in serum and placenta in mice during pregnancy. Interestingly, we observed increased serum chemerin levels and decreased GPR1 expression in placenta of high-fat-diet-fed mice compared with chow-fed mice at gestational day 18. GPR1 protein and gene levels were significantly decreased in gestational diabetes mellitus (GDM) patient placentas. Therefore, we hypothesized that chemerin/GPR1 signaling might participate in the pathogenic mechanism of GDM. We investigated the role of GPR1 in carbohydrate homeostasis during pregnancy using pregnant mice transfected with small interfering RNA for GPR1 or a negative control. GPR1 knockdown exacerbated glucose intolerance, disrupted lipid metabolism, and decreased β-cell proliferation and insulin levels. Glucose transport protein-3 and fatty acid binding protein-4 were downregulated with reducing GPR1 in vivo and in vitro via phosphorylated AKT pathway. Taken together, our findings first demonstrate the expression of GPR1, the characterization of its direct biological effects in humans and mice, as well as the molecular mechanism that indicates the role of GPR1 signaling in maternal metabolism during pregnancy, suggesting a novel feedback mechanism to regulate glucose balance during pregnancy, and GPR1 could be a potential target for the detection and therapy of GDM.

scholarly journals Limited role of CD28-mediated signals in T helper subset differentiation.

1996 ◽  
Vol 184 (3) ◽  
pp. 803-810 ◽  
Author(s):  
D R Brown ◽  
J M Green ◽  
N H Moskowitz ◽  
M Davis ◽  
C B Thompson ◽  
...  
Keyword(s):  
T Cell Differentiation ◽  
Interleukin 4 ◽  
T Helper ◽  
T Helper 1 ◽  
Absolute Requirement ◽  
Costimulatory Signals ◽  
Draining Lymph Nodes

The role of CD28-mediated signals in T helper cell maturation is not fully understood. We tested the requirement for costimulation through CD28 in several systems of CD4+, T cell differentiation. In vivo priming of mice with genetic disruption of CD28 (CD28-/-) yielded normal levels of antigen-specific interferon gamma production but markedly diminished levels of interleukin 4 (IL-4) after in vitro restimulation. In response to the pathogenic microbe, Leishman a major, C57BL6 CD28-/- mice were fully capable of controlling infection and exhibited a normal T helper 1 response. BALB/c CD28-/- mice unexpectedly exhibited normal susceptibility to L. major. BALB/c CD28-/- mice developed high levels of IL-4 mRNA and protein induction in the draining lymph nodes. In addition, susceptibility of BALB/c CD28-/- mice was reversed by neutralization of IL-4 in vivo. We also activated transgenic CD28-bearing T cells from the BALB and C57BL background in vitro in the presence of CTLA4Ig. BALB cells had greater IL-4 producing capacity than C57BL cells in the absence of costimulation. Diverse factors including costimulatory signals, genetic polymorphism, and the nature of the immunogen all influence T helper phenotype commitment, but these results provide evidence that CD28 is not an absolute requirement for generating either Th1 or Th2 responses.

scholarly journals Interleukin-10 and Antigen-Presenting Cells Actively Suppress Th1 Cells in BALB/c Mice Infected with the Filarial Parasite Brugia pahangi

1999 ◽  
Vol 67 (4) ◽  
pp. 1599-1605 ◽  
Author(s):  
Julie Osborne ◽  
Eileen Devaney
Keyword(s):  
Interleukin 10 ◽  
Interleukin 4 ◽  
Th1 Cells ◽  
Spleen Cells ◽  
Third Stage ◽  
Antigen Presenting ◽  
Th1 Cytokines

ABSTRACT Infection with the third-stage larvae (L3) of the filarial nematodeBrugia results in a Th2-biased immune response in mice and humans. Previously we have shown that the production of interleukin 4 (IL-4) is critical for down-regulating polyclonal Th1 responses in L3-infected mice. However, the in vitro neutralization of IL-4 did not fully recover the defective polyclonal Th1 responses, nor did it result in the production of any antigen (Ag)-specific Th1 cytokines, suggesting that perhaps infection with L3 does not result in priming of Th1 cells in vivo. In this study, we analyzed the role of IL-10 and Ag-presenting cells (APCs) in the spleen as additional factors controlling the Th2 bias in infected mice. Our data show that IL-10 and APCs also contribute to the suppression of mitogen-driven Th1 responses of spleen cells from infected mice. In addition, the neutralization of IL-10 or the replacement of the resident APC population from spleen cell cultures resulted in the production of Ag-specific Th1 cytokines. Irradiated spleen cells from either L3-infected or uninfected mice were able to restore Ag-specific Th1 responses in vitro. Therefore, it appears that Brugia-reactive Th1 cells are primed following infection with L3, but are actively suppressed in vivo by a mechanism that involves IL-10 and the resident APC population, but not IL-4. These results indicate that a complex interplay of cytokines and cell populations underscores the Th2-polarized response in L3-infected mice.

scholarly journals Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model

2007 ◽  
Vol 56 (8) ◽  
pp. 1047-1051 ◽  
Author(s):  
Sean T. Byrne ◽  
Steven M. Denkin ◽  
Peihua Gu ◽  
Eric Nuermberger ◽  
Ying Zhang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Term Treatment ◽  
New Drugs ◽  
Bacteriostatic Effect ◽  
Short Term ◽  
Short Term Treatment ◽  
Neutral Conditions

There is an urgent need for the development of new drugs that are active against drug-resistant Mycobacterium tuberculosis strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity in vitro. This study evaluated ketoconazole (KTC) for activity against M. tuberculosis. The MIC of KTC for different M. tuberculosis strains ranged from 8 to 16 μg ml−1 under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli in vitro when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg−1 led to an inhibitory serum concentration 2 h after administration. The in vivo activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.

scholarly journals Cellular and Molecular Pathways Leading to External Root Resorption

2016 ◽  
Vol 96 (2) ◽  
pp. 145-152 ◽  
Author(s):  
A. Iglesias-Linares ◽  
J.K. Hartsfield
Keyword(s):  
Root Resorption ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Molecular Pathways ◽  
Apical Root Resorption ◽  
External Root Resorption ◽  
External Apical Root Resorption

External apical root resorption during orthodontic treatment implicates specific molecular pathways that orchestrate nonphysiologic cellular activation. To date, a substantial number of in vitro and in vivo molecular, genomic, and proteomic studies have supplied data that provide new insights into root resorption. Recent mechanisms and developments reviewed here include the role of the cellular component—specifically, the balance of CD68+, iNOS+ M1- and CD68+, CD163+ M2-like macrophages associated with root resorption and root surface repair processes linked to the expression of the M1-associated proinflammatory cytokine tumor necrosis factor, inducible nitric oxide synthase, the M1 activator interferon γ, the M2 activator interleukin 4, and M2-associated anti-inflammatory interleukin 10 and arginase I. Insights into the role of mesenchymal dental pulp cells in attenuating dentin resorption in homeostasis are also reviewed. Data on recently deciphered molecular pathways are reviewed at the level of (1) clastic cell adhesion in the external apical root resorption process and the specific role of α/β integrins, osteopontin, and related extracellular matrix proteins; (2) clastic cell fusion and activation by the RANKL/RANK/OPG and ATP-P2RX7-IL1 pathways; and (3) regulatory mechanisms of root resorption repair by cementum at the proteomic and transcriptomic levels.

scholarly journals Transcription factor signal transducer and activator of transcription 6 (STAT6) is an inhibitory factor for adult myogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mitsutoshi Kurosaka ◽  
Yuji Ogura ◽  
Shuichi Sato ◽  
Kazuhisa Kohda ◽  
Toshiya Funabashi
Keyword(s):  
Transcription Factor ◽  
Knockout Mice ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 4 ◽  
Signal Transducer ◽  
Culture Dish ◽  
Myotube Formation

Abstract Background The signal transducer and activator of transcription 6 (STAT6) transcription factor plays a vitally important role in immune cells, where it is activated mainly by interleukin-4 (IL-4). Because IL-4 is an essential cytokine for myotube formation, STAT6 might also be involved in myogenesis as part of IL-4 signaling. This study was conducted to elucidate the role of STAT6 in adult myogenesis in vitro and in vivo. Methods Myoblasts were isolated from male mice and were differentiated on a culture dish to evaluate the change in STAT6 during myotube formation. Then, the effects of STAT6 overexpression and inhibition on proliferation, differentiation, and fusion in those cells were studied. Additionally, to elucidate the myogenic role of STAT6 in vivo, muscle regeneration after injury was evaluated in STAT6 knockout mice. Results IL-4 can increase STAT6 phosphorylation, but STAT6 phosphorylation decreased during myotube formation in culture. STAT6 overexpression decreased, but STAT6 knockdown increased the differentiation index and the fusion index. Results indicate that STAT6 inhibited myogenin protein expression. Results of in vivo experiments show that STAT6 knockout mice exhibited better regeneration than wild-type mice 5 days after cardiotoxin-induced injury. It is particularly interesting that results obtained using cells from STAT6 knockout mice suggest that this STAT6 inhibitory action for myogenesis was not mediated by IL-4 but might instead be associated with p38 mitogen-activated protein kinase phosphorylation. However, STAT6 was not involved in the proliferation of myogenic cells in vitro and in vivo. Conclusion Results suggest that STAT6 functions as an inhibitor of adult myogenesis. Moreover, results suggest that the IL-4-STAT6 signaling axis is unlikely to be responsible for myotube formation.

scholarly journals Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 688-699 ◽  
Author(s):  
BA Araneo ◽  
T Dowell ◽  
M Diegel ◽  
RA Daynes
Keyword(s):  
T Cells ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Activated T Cells ◽  
Direct Exposure ◽  
Accessory Cells ◽  
Males And Females

The present study examined the effects of the androgen steroid, dihydrotestosterone (DHT), on murine T-cell production of a number of lymphokines. Direct exposure of murine T cells to DHT in vitro was found to reduce the amount of interleukin-4 (IL-4), IL-5, and gamma- interferon (gamma IFN) produced after activation with anti-CD3 without affecting the production of IL-2. Exposure of T cells to either androstenedione or testosterone (the metabolic precursors of DHT) affected no change in the biosynthesis of either of these lymphokines. We have determined that macrophages possess 5 alpha-reductase, and are thus competent to metabolize testosterone to DHT. This physicochemical information is complemented by a functional analysis of macrophage metabolism of testosterone. By incubating bone marrow macrophages with testosterone, before their use as accessory cells, the IL-4 and IL-5 producing potential of the activated T cells cocultured with them was depressed. That the observed effect was mediated by the conversion of testosterone to DHT was further corroborated by illustrating that the inhibition of IL-4 production was abrogated if 4MA, a specific 5 alpha- reductase inhibitor, was added to macrophage cultures containing testosterone. The biologic role of DHT in lymphokine and immune response regulation in vivo was addressed using several lines of investigation. First, transdermal delivery of DHT to groups of mice altered the capacity of T cells residing in the draining lymph nodes, only, to produce lymphokines. Second, treatment of either aged mice or the T cells isolated from them with a combination of dehydroepiandrosterone and DHT restored the capacity of their T cells to produce IL-2, IL-4, and gamma IFN to levels equivalent to that of younger mice. Finally, we observed a difference between males and females of a given age to produce IL-2, IL-4, and gamma IFN, with both IL-4 and gamma IFN production being elevated in females. Collectively, our findings indicate that DHT, similar to other steroid hormones, may play an important role in lymphokine regulation in vivo.

Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2277-2283 ◽  
Author(s):  
Veronika Sexl ◽  
Roland Piekorz ◽  
Richard Moriggl ◽  
Juerg Rohrer ◽  
Michael P. Brown ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Target Cells ◽  
Interleukin 7 ◽  
And Function ◽  
Deficient Mice

Abstract The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

scholarly journals Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 688-699 ◽  
Author(s):  
BA Araneo ◽  
T Dowell ◽  
M Diegel ◽  
RA Daynes
Keyword(s):  
T Cells ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Activated T Cells ◽  
Direct Exposure ◽  
Accessory Cells ◽  
Males And Females

Abstract The present study examined the effects of the androgen steroid, dihydrotestosterone (DHT), on murine T-cell production of a number of lymphokines. Direct exposure of murine T cells to DHT in vitro was found to reduce the amount of interleukin-4 (IL-4), IL-5, and gamma- interferon (gamma IFN) produced after activation with anti-CD3 without affecting the production of IL-2. Exposure of T cells to either androstenedione or testosterone (the metabolic precursors of DHT) affected no change in the biosynthesis of either of these lymphokines. We have determined that macrophages possess 5 alpha-reductase, and are thus competent to metabolize testosterone to DHT. This physicochemical information is complemented by a functional analysis of macrophage metabolism of testosterone. By incubating bone marrow macrophages with testosterone, before their use as accessory cells, the IL-4 and IL-5 producing potential of the activated T cells cocultured with them was depressed. That the observed effect was mediated by the conversion of testosterone to DHT was further corroborated by illustrating that the inhibition of IL-4 production was abrogated if 4MA, a specific 5 alpha- reductase inhibitor, was added to macrophage cultures containing testosterone. The biologic role of DHT in lymphokine and immune response regulation in vivo was addressed using several lines of investigation. First, transdermal delivery of DHT to groups of mice altered the capacity of T cells residing in the draining lymph nodes, only, to produce lymphokines. Second, treatment of either aged mice or the T cells isolated from them with a combination of dehydroepiandrosterone and DHT restored the capacity of their T cells to produce IL-2, IL-4, and gamma IFN to levels equivalent to that of younger mice. Finally, we observed a difference between males and females of a given age to produce IL-2, IL-4, and gamma IFN, with both IL-4 and gamma IFN production being elevated in females. Collectively, our findings indicate that DHT, similar to other steroid hormones, may play an important role in lymphokine regulation in vivo.

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