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Systemic lupus erythematosus (SLE) is an inflammatory disorder related to immunity dysfunction. The Th1 cell family including Th1 cells, transcription factor T-bet, and related cytokines IFNγ, TNFα, IL-2, IL-18, TGF-β, and IL-12 have been widely discussed in autoimmunity, such as SLE. In this review, we will comprehensively discuss the expression profile of the Th1 cell family in both SLE patients and animal models and clarify how the family members are involved in lupus development. Interestingly, T-bet-related age-associated B cells (ABCs) and low-dose IL-2 treatment in lupus were emergently discussed as well. Collection of the evidence will better understand the roles of the Th1 cell family in lupus pathogenesis, especially targeting IL-2 in lupus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Wang, Chen, Xu and Huang.)

Th cells play an important role in pathogenesis of type 1 diabetes (T1D). Peripheral blood mononuclear cells were isolated from peripheral blood samples from newly diagnosed (ND), 1-year (1YD), and 5-year T1D (5YD) patients (n:8 of each group), 8 healthy controls (HC), and cultured for 24 h under unstimulated (US) and stimulated conditions. Cell ratios of Th1, Th2, Th17, Treg, and intracellular levels of IFN-γ, TNF-α, IL-10, TGF-β, IL-5, IL-13, IL-17, and IL-21 cytokines were evaluated using the flow cytometry. mRNA expressions of transcription factors T-bet, GATA3, ROR-γt, and FOXP3 of these cells were determined by real-time PCR. Reduced CD4 + CD25 high cell ratios were detected in ND. CD4 + CD25 high cells were found to be reduced in ND and 1YD compared to HC under IL-2-stimulated conditions. Intracellular IFN-γ and TNF-α levels were low in all patients under US and IL-12-stimulated conditions. IL-17A and IL-21 were found to be high in patients with IL-6-stimulated conditions. Expressions of IL-10 and TGF-β have been observed to be reduced in patients. Th1/Th2, Th17/Treg, and Th1/Treg ratios were higher in patient groups. FOXP3 and GATA3 mRNA expressions were found to be low in patients, while RORγt and T-bet mRNA levels were higher than HC. Th1, Th17, and Treg cells and their cytokines have been shown to be associated with type 1 diabetes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Conventional dendritic cells (cDCs) can integrate multiple stimuli from the environment and provide three separate outputs in terms of antigen presentation, costimulation, and cytokine production; this guides the activation, expansion, and differentiation of distinct functional T helper subsets. Accordingly, the current dogma posits that T helper cell specification requires these three signals in sequence. Data show that T helper 2 (Th2) cell differentiation requires antigen presentation and costimulation from cDCs but does not require polarizing cytokines. In this opinion article, we propose that the 'third signal' driving Th2 cell responses is, in fact, the absence of polarizing cytokines; indeed, the secretion of the latter is actively suppressed in cDCs, concomitant with acquired pro-Th2 functions., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The α-L-guluronic acid (G2013), is a novel immunosuppressive drug (PCT/EP2017/067920). One of the most popular ideas in designing drugs for multiple sclerosis (MS) is to restrict the main inflammation-related lymphocytes and cytokines. The foremost problems with conventional drugs are their side effects and low efficacy. In order to rectify these problems, we examined the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, in MS patients PBMCs. RNA was extracted from peripheral blood mononuclear cell (PBMC) of 12 relapsing-remitting MS patients and 12 healthy volunteers and the effect of two doses of G2013 on the gene expression of IFN-γ, IL-17, IL-22, T-bet, RORC, and AHR, were assessed by real-time PCR. Overall, the results show that G2013 is able to significantly reduce the gene expression of IL-22, AHR, RORC, and T-bet. Collectively, G2013 might be considered and studied as a new drug of possible use to MS patients due to its immunosuppressive property on some of the main inflammatory cytokine and transcription factors., (© 2020 Wiley Periodicals, Inc.)

Natural killer (NK) cells are cells of the innate immunity and play an important role in the defense against viral infections and cancer, but also contribute to shaping adaptive immune responses. Long-lived tissue-resident NK cells have been described in man and mouse, particularly in the liver, contributing to the idea that the functional palette of NK cells may be broader than originally thought, and may include memory-like responses and maintaining tissue homeostasis. Remarkably, liver resident (lr)NK cells in man and mouse show substantial species-specific differences, in particular reverse expression patterns of the T-box transcription factors Eomesodermin (Eomes) and T-bet (Eomes high T-bet low in man and vice versa in mouse). In pig, compared to blood NK cells which are CD3 - CD8α high cells, the porcine liver contains an abundant additional CD3 - CD8α dim NK cell subpopulation. In the current study, we show that this porcine CD3 - CD8α dim liver NK population is highly similar to its human lrNK counterpart and therefore different from mouse lrNK cells. Like human lrNK cells, this porcine NK cell population shows an Eomes high T-bet low expression pattern. In addition, like its human counterpart, the porcine liver NK population is CD49e - and CXCR6 + . Furthermore, the porcine Eomes high T-bet low liver NK cell population is able to produce IFN-γ upon IL-2/12/18 stimulation but lacks the ability to kill K562 or pseudorabies virus-infected target cells, although limited degranulation could be observed upon incubation with K562 cells or upon CD16 crosslinking. All together, these results show that porcine Eomes high T-bet low NK cells in the liver strongly resemble human lrNK cells, and therefore indicate that the pig may represent a unique model to study the function of these lrNK cells in health and disease., (Copyright © 2019 De Pelsmaeker, Denaeghel, Hermans and Favoreel.)

Ethnopharmacological Relevance: Solanum paniculatum L., popularly known as jurubeba, is a common subtropical plant from Brazil, Paraguay, Bolivia and Argentina, that is used in folk medicine for the treatment of anemia, gastrointestinal disorders and inflammatory conditions in general. In addition to that, an ethnobotanical survey in "Todos os Santos" Bay have pointed out S. paniculatum as an herb to treat asthma. Previous publications have shown that S. paniculatum possesses antibiotic, antioxidant and modulatory effects on gastric acid secretion; however, its anti-inflammatory potential remains unexplored., Aim of the Study: Herein, we analyzed the S. paniculatum fruits hexane extract (SpE) for the presence of stigmasterol and β-sitosterol and investigated the anti-inflammatory effect of SpE in vitro., Materials and Methods: SpE was subjected to high-performance liquid chromatography (HPLC) for standardization and quantification of stigmasterol and β-sitosterol. Spleen cells from BALB/c mice were cultivated and stimulated with pokeweed mitogen and also exposed to 15, 30 and 60µg/mL of SpE. Following treatment, levels of IFN-γ, IL-4 and IL-10 in the culture supernatants were assessed by ELISA. We also evaluated nitric oxide (NO) production by murine LPS-stimulated peritoneal macrophages using the Griess technique. In addition, the ability of SpE to stabilize membranes was assessed using a model of hemolysis induced by heat on murine erythrocytes. Gene expression of Th1-cell-specific Tbx21 transcription factor (TBET), zinc-finger transcription factor-3 (GATA3), and nuclear factor-κB (NFKB) in murine spleen cells were assessed by quantitative Polymerase Chain Reaction (qRT-PCR)., Results: SpE at 15, 30 and 60µg/mL significantly attenuated cell proliferation, decreased IL-4 release, reduced NO production and improved erythrocyte membrane stabilization in a concentration-dependent manner. SpE was also able to decrease the release of IFN-γ without altering IL-10 levels. The mechanism whereby SpE decreased inflammatory markers may be related to the reduction of NFKB, TBET and GATA3 gene expression., Conclusions: This study is the first to test the anti-inflammatory action of S. paniculatum. Herein, we provided evidence for the popular use of S. paniculatum in inflammatory conditions. Additional studies must be conducted to further explore the anti-inflammatory potential of SpE and to elucidate possible clinical applications., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Bronchial asthma is a chronic airway inflammatory disease that involves T lymphocytes., Methods: In order to explore the effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4(+) CD25(+) Foxp3(+) Treg in asthma Balb/c mouse, we constructed acute asthma model with ovalbumin to observe the mouse behavior change in Balb/c mice. The expression of GATA-3 mRNA and T-bet mRNA was measured by real-time PCR. The proportion of CD4(+) CD25(+) Foxp3(+) Treg/CD4(+) was determined by flow cytometry., Results: The results demonstrated that oral gavage with Lactobacillus salivarius before sensitization could alleviate the clinical symptoms, airway hyper-reactivity and airway inflammation in asthma mouse to some extent; Lactobacillus salivarius may improve the imbalance of Th1/Th2 in asthma mouse through increasing the expression of T-bet mRNA at the transcriptional level and inhibiting the expression of GATA-3 mRNA simultaneously., Conclusion: CD4(+) CD25(+) Foxp3(+) Treg cells may be involved in the pathogenesis of bronchial asthma, and may be the upstream regulatory mechanism of the improvement of Th1/Th2 imbalance by Lactobacillus salivarius.

We found that after stimulation for a few hours, memory but not naive CD4(+) T cells produced a large amount of IFN-γ; however, the mechanism of rapid response of memory CD4(+) T cells remains undefined. We compared the expression of transcription factors in resting or activated naive and memory CD4(+) T cells and found that T-bet, but not pSTAT-1 or pSTAT-4, was highly expressed in resting memory CD4(+) T cells and that phenotypic characteristics of T-bet(+)CD4(+) T cells were CD45RA(low)CD62L(low) CCR7(low). After short-term stimulation, purified memory CD4(+) T cells rapidly produced effector cytokines that were closely associated with the pre-existence of T-bet. By contrast, resting naive CD4(+) T cells did not express T-bet, and they produced cytokines only after sustained stimulation. Our further studies indicated that T-bet was expressed in the nuclei of resting memory CD4(+) T cells, which might have important implications for rapid IFN-γ production. Our results indicate that the pre-existence and nuclear mobilization of T-bet in resting memory CD4(+) T cells might be a possible transcriptional mechanism for rapid production of cytokines by human memory CD4(+) T cells., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Staining of transcription factors (TFs) together with retention of fluorescent reporter proteins is hindered by loss of fluorescence using current available methods. In this study, it is shown that current TF staining protocols do not destroy fluorescent proteins (FPs) but rather that fixation is not sufficient to retain FPs in the cytosol of the permeabilized cells. In this article, a simple and reliable protocol is elaborated, which allows efficient TF and cytokine staining while retaining FPs inside fixed cells., (© 2014 International Society for Advancement of Cytometry.)

Systemic lupus erythematosus (SLE) is an inflammatory disorder related to immunity dysfunction. The Th1 cell family including Th1 cells, transcription factor T-bet, and related cytokines IFNγ, TNFα, IL-2, IL-18, TGF-β, and IL-12 have been widely discussed in autoimmunity, such as SLE. In this review, we will comprehensively discuss the expression profile of the Th1 cell family in both SLE patients and animal models and clarify how the family members are involved in lupus development. Interestingly, T-bet-related age-associated B cells (ABCs) and low-dose IL-2 treatment in lupus were emergently discussed as well. Collection of the evidence will better understand the roles of the Th1 cell family in lupus pathogenesis, especially targeting IL-2 in lupus. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) has been considered a Th2- and Th17-related disease. However, anti-IL-12/23 p40 antibody, which blocks Th1 and Th17 cell induction and maintenance, has shown efficacy in treating UC, suggesting that UC might not be a prototypical Th2 and Th17 cell-mediated autoimmune disease. To verify how the immune responses in UC patients interact with each other, we analyzed the cytokine expression and transcription factors involved in the Th1, Th2, and Th17 responses. The mucosal expression of 19 cytokines and transcription factors related to Th1, Th2, and Th17 cells, as well as Tregs, were measured by quantitative polymerase chain reaction using endoscopic biopsy specimens from inflamed colons of UC patients. A correlation analysis between the cytokines and transcription factors was conducted. The characteristic cytokine profile in UC patients has two immune response clusters: Th17-related responses and Th1-/Th2-related responses. IL-23 showed a weaker association with Th17 cell-related cytokines and transcription factor RORC and a much stronger correlation with T-bet and GATA3. In the high-IL-23-expression group, the rate of chronic continuous type was higher and the remission rate lower than in the low-IL-23-expression group. IL-23 may be a very important cytokine for evaluating the UC disease condition, as the expression of IL-23 is associated with certain clinical characteristics of UC patients. A unique association between IL-23 and T-bet/GATA3 might play a key role in the pathogenesis of UC. [ABSTRACT FROM AUTHOR]

Gout is sterile joint inflammation triggered by the damaging effects of monosodium urate (MSU) crystals accumulation. Previous studies suggest transcription factor T-bet plays an important role in inflammatory arthritis. Notably, mice lacking T-bet markedly reduced joint inflammation of rheumatoid arthritis models, however, the involvement of T-bet in gouty inflammation has yet to be clarified. Here, we took advantage of T-bet knockout (KO) mice to investigate the role of T-bet in the pathogenesis of MSU-induced gout inflammation. T-bet KO and wild type (WT) mice were used for models of acute inflammation induced with MSU crystals, including footpad, air pouch and peritonitis models. Inflammatory cytokines and phagocytosis were detected in bone-marrow-derived macrophages (BMDMs) from T-bet KO and WT mice treated with MSU crystals in vitro. In addition, T-bet expression in peripheral blood mononuclear cells (PBMCs) from gout patients was measured, as well as plasma inflammatory cytokines. We found that the levels of interleukin (IL)-17, IL-23, and interferon-γ were reduced, but tumor necrosis factor-α was not, in BMDMs from T-bet KO compared with WT mice after MSU challenge in vitro, as well as MSU phagocytosis. In comparison with WT mice in vivo, the swelling index of T-bet KO mice was significantly decreased in the footpad model. T-bet deficiency also dramatically relieved MSU-induced inflammatory cell infiltration in peritonitis and air pouch models in vivo, and as well as the IL-1β levels of air pouch lavage fluid (APLF). In addition, plasma IL-17 and IL-23 levels were elevated in acute gout, whereas protein levels of T-bet were downregulated in PBMCs from acute gout patients and intercritical gout treated with MSU crystals in vitro as well. Transcription factor T-bet deficiency protects against MSU-induced gouty inflammation, suggesting that downregulation of T-bet could be a protective strategy and contribute to spontaneous remission of inflammation in acute gout.

Context: Oxymatrine (OMT) has various pharmacological effects, including immune reaction regulation, anti-inflammation and anti-hypersensitive reaction. Objective: This is the first report to investigate the molecular mechanism of OMT function in l-arginine (Arg)-induced acute pancreatitis (AP) involving intestinal injury. Materials and methods: Rat pancreatic AR42J and small intestinal IEC-6 cells were treated with Arg (200–800 µM) for 48 h plus OMT (4 mg/mL) treatment. Thirty adult Wistar rats were randomly assigned to control (saline), AP (i.p. of 250 mg/100 g body weight Arg) and OMT (i.p. injection of 50 mg/kg b.w. OMT every 6 h following Arg). Both cells and rats were harvested at 48 h. Results: Arg-induced cell proliferation in both rats AR42J (EC50 633.9 ± 31.4 µM) and IEC-6 cells (EC50 571.3 ± 40.4 µM) in a dose-dependent manner, which was significantly inhibited by OMT (4 mg/mL). Meanwhile, Arg (600 µM) induced expression of proinflammatory cytokines (TNF-α, IL-6, IL-1β, NF-κB, IL-17A/IL-17F and IFN-γ) and activation of p-p38/p-ERK in vitro, which was reversed by OMT. In vivo, OMT (50 mg/kg) inhibited 250 mg/100 g of Arg-induced AP involving intestinal injury, including inhibiting Arg-induced inflammatory in pancreas and intestine, inhibiting Arg-induced increase of TNF-α, IL-6, IL-1β, NF-κB and p-p38/p-ERK-MAPK signalling, and inhibiting Arg-induced increase of IL-17A/IL-17F, IFN-γ, ROR-γt and T-bet. Meanwhile, OMT inhibited Arg-induced expression of CD44 and CD55 in intestinal injury. Discussion and conclusions: OMT protects against Arg-induced AP involving intestinal injury via regulating Th1/Th17 cytokines and MAPK/NF-κB signalling, which is a promising therapeutic agent in clinics. [ABSTRACT FROM AUTHOR]

T‐bet is a major transcription factor increasing inflammatory responses in the immune system. Recently, it has been shown that this factor leads to inflammation in cardiovascular disease (CVD). In this study, we examine the dual role of T‐bet in inducing and suppressing inflammatory reactions as well as angiogenesis induction due to inflammatory cytokines in CVD. Relevant literature was identified by a Pubmed search (1992–2018) of English‐language papers using the terms "T‐bet," "Cardiovascular disease," "Immune response," and "Angiogenesis." Although T‐bet causes differentiation of Th1 cells and activation of immune cells such as NK and DC, it suppresses inflammatory responses and replaces damaged vessels with new ones by activating regulatory T‐cells and stimulating angiogenesis. It can be stated that T‐bet acts as double‐edged sword. Therefore, the identification of pathways that can increase the function of T‐bet in activating Tregs and inducing angiogenesis might be used as a new therapeutic option in future investigations. HIGHLIGHTS: T‐bet factor plays an essential role in the regulation of immune responses in CVD.T‐bet factor induces angiogenesis through the mediation of inflammatory cytokines.T‐bet can be effective in CVD pathogenesis via interaction with other transcription factors. This manuscript attempts to discuss effect of T‐bet on function of immune cell in cardiovascular disease. Also we evaluation of relationship between T‐bet and angiogenesis by inflammatory cytokine and endothelial progenitor cells. [ABSTRACT FROM AUTHOR]

Gout is sterile joint inflammation triggered by the damaging effects of monosodium urate (MSU) crystals accumulation. Previous studies suggest transcription factor T-bet plays an important role in inflammatory arthritis. Notably, mice lacking T-bet markedly reduced joint inflammation of rheumatoid arthritis models, however, the involvement of T-bet in gouty inflammation has yet to be clarified. Here, we took advantage of T-bet knockout (KO) mice to investigate the role of T-bet in the pathogenesis of MSU-induced gout inflammation. T-bet KO and wild type (WT) mice were used for models of acute inflammation induced with MSU crystals, including footpad, air pouch and peritonitis models. Inflammatory cytokines and phagocytosis were detected in bone-marrow-derived macrophages (BMDMs) from T-bet KO and WT mice treated with MSU crystals in vitro. In addition, T-bet expression in peripheral blood mononuclear cells (PBMCs) from gout patients was measured, as well as plasma inflammatory cytokines. We found that the levels of interleukin (IL)-17, IL-23, and interferon-γ were reduced, but tumor necrosis factor-α was not, in BMDMs from T-bet KO compared with WT mice after MSU challenge in vitro , as well as MSU phagocytosis. In comparison with WT mice in vivo , the swelling index of T-bet KO mice was significantly decreased in the footpad model. T-bet deficiency also dramatically relieved MSU-induced inflammatory cell infiltration in peritonitis and air pouch models in vivo , and as well as the IL-1β levels of air pouch lavage fluid (APLF). In addition, plasma IL-17 and IL-23 levels were elevated in acute gout, whereas protein levels of T-bet were downregulated in PBMCs from acute gout patients and intercritical gout treated with MSU crystals in vitro as well. Transcription factor T-bet deficiency protects against MSU-induced gouty inflammation, suggesting that downregulation of T-bet could be a protective strategy and contribute to spontaneous remission of inflammation in acute gout. [ABSTRACT FROM AUTHOR]

Transcription factors regulate various developmental and functional aspects of B cells. T-bet is a recently appreciated transcription factor associated with “Age-associated B cells” or ABCs, the development of autoimmunity, and viral infections. T-bet expression is favored by nucleic acid-containing antigens and immune complexes and is regulated by interplay between various cytokines, notably, the TFH cytokines IL-21, IL-4 and IFNγ. Adaptive signals by themselves cannot upregulate T-bet; however, they have a synergistic effect on induction of T-bet by innate receptors. The functional role of T-bet+ B cells is unclear, although it is known that T-bet promotes class switching to IgG2a/c. It is likely T-bet serves dichotomous roles in B cells, promoting pathogenic autoreactive antibodies on one hand but mediating microbial immunity on the other, making it a target of interest in both therapeutic and prophylactic settings. [ABSTRACT FROM AUTHOR]

Photodynamic therapy ( PDT) has proven to be an effective alternative for the treatment of cutaneous leishmaniasis. Skin lesions consist of ulcers with well-defined raised edges, and granular floor. Th1 immune response is the protective profile in patients infected with Leishmania. In this study, the photodynamic therapy with 5-aminolevulinic acid, the parasitic load, and the modulation of the immune response was evaluated in mice infected with Leishmania braziliensis. Balb/c mice were infected with L. braziliensis and subsequently treated with three sections of PDT. The parasite load and mRNA expression of cytokines ( IFN-γ, IL-4, IL-17, IL-22, IL-27, IL-10) and transcription factors ( GATA-3, Foxp3 and T-bet) were analysed by quantitative PCR. The parasite load in the treated group was significantly lower than in the untreated group ( P<.0001); in PDT treated animals, we observed an increase in IFN-γ and T-bet mRNA ( P=.012 and P=.0071). There was a significant reduction in mRNA expression of IL-22 associated with an increased expression of IL-27 mRNA in the animals treated with light only ( P=.0001). 5- ALA associated with photodynamic therapy promotes a reduction in parasite load and an increased expression of IFN-γ and T-bet mRNA. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) function in producing effector cytokines in response to pathogenic infections. However, the roles and related mechanisms of the ILC subpopulations, ILC1 and ILC2, which mirror Th1 and Th2 in adaptive immunity, remain unclear. In this study, we found the markedly elevated levels of the ILC1 transcription factor T-bet, the effector cytokine IFN-γ and the IL/receptor signaling molecules IL-12/IL-12R, which are indispensable for ILC1 differentiation, in the helper ILCs of chronic hepatitis B (CHB) patients. The elevated level of the ILC1 population was significantly associated with hepatic damage in CHB patients, and was not related to telbivudine treatment. In contrast, although we also observed elevated levels of ILC2-related factors, including IL-33, ST2, GATA3 and IL-13 in helper ILCs, the extent of elevation shown by each was lower than that shown by the ILC1-related factors. Furthermore, the activity of the ILC2s did not correlate with either HBV copies or liver damage. The findings of this study suggest potential pro-inflammatory roles for ILC1s in CHB pathogenesis, potentiating these cells and their related molecules as targets of diagnostic, prognostic and/or therapeutic strategies for hepatitis B. [ABSTRACT FROM AUTHOR]

Engaging the T cell receptor (TCR) with peptide:MHC complexes initiates a cascade of signaling events that activates T cells in an antigen-specific manner. It is now clear that multiple inputs, including the strength of TCR signaling, co-stimulation, and the cytokine environment, impact T cell specialization decisions in the context of specific pathogenic encounters. Additionally, it is now appreciated that these same stimuli direct cellular metabolism programs. In this review, we will discuss how TCR-signaling events coordinate cellular metabolism and specialization gene programs in T cells. [ABSTRACT FROM AUTHOR]

T-bet and GATA-3 are known to regulate cytokine expression in T lymphocytes, and cytokines have been implicated in endometrial regulation and implantation. Previous work showed that female steroid hormones modulate the expression of T-bet in endometrial epithelial cells, suggesting a mechanism for local immune regulation in the human endometrium. We hypothesized that stromal cells are involved in immune regulation, as they have been shown to exert paracrine effects on other endometrial cells and compartments and also secrete cytokines. The objective of this study was to examine the modulation of the gene expression of T-bet and GATA-3, and of the cytokines interferon γ (IFN-γ) and interleukin 4 (IL-4), by female steroid hormones, in human endometrial stromal cells (HESC) in long-term cultures (30 days) mimicking the normal menstrual cycle. T-bet and GATA-3 messenger RNA (mRNA) expression was detected by real-time polymerase chain reaction, and intracellular protein production was demonstrated by immunoblotting. In addition, secretion of IL-4 and IL-15 was measured by enzyme-linked immunosorbent assay. T-bet and IL-4 mRNA expression increased and GATA-3 decreased under decidualization conditions; IFN-γ was not detected. Secretion of IL-15 increased during decidualization, and IL-15 upregulated T-bet gene expression. In conclusion, gene expression of T-bet and GATA-3 by endometrial stromal cells is under hormonal conditions mimicking decidualization, and the results are consistent with an autocrine regulatory mechanism of IL-15 secretion and T-bet expression. [ABSTRACT FROM AUTHOR]

Abstract: The association of T helper (Th) 1 cells with obesity is well documented in both animals and humans. The T-box transcription factor (T-bet) is known as the transcription factor that is responsible for the development of Th1 cells. However, the role of T-bet in obesity has never been elucidated. The present study aimed to investigate the regulatory function of T-bet on obesity in mice. Th1 cytokine levels were decreased, whereas Th2 cytokine level and GATA-3 messenger RNA (mRNA) expression were increased in T-bet knockout (KO) mice. T-bet KO male mice induced obesity as a result of increased body weight and food efficiency despite the fact that they feed a control diet. T-bet KO mice have an increase in weight of white adipose tissue and levels of triacylglyceride and low-density lipoprotein cholesterol. Interestingly, the expression levels of energy expenditure-related genes were decreased in T-bet KO mice. Both T-bet KO male and female mice had impaired glucose tolerance. In white adipose tissue, leptin, the increase in peroxisome proliferator receptor-γ and CAAT/enhancer-binding protein α mRNA expressions in T-bet KO mice was more than that in wild-type mice. Furthermore, we found that the level of interleukin (IL)-6 mRNA expression in white adipose tissue was elevated in T-bet KO mice but not IL-1β and tumor necrosis factor-α. IL-6 mRNA expression was increased in adipocyte fraction and stromal vascular fraction in white adipose tissue of T-bet KO mice. Taken together, our results reveal that T-bet may affect obesity through the regulation of IL-6 expression in adipocytes of white adipose tissue. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Fenugreek (Trigonella foenum-graecum L.) has a wide variety of therapeutic properties for allergic and inflammatory diseases and is used as a traditional functional food, but its antiallergenic mechanism in these diseases is yet to be clearly elucidated. Aim: In the present study, we investigated the antiallergic activity of fenugreek extract using trimellitic anhydride (TMA)-induced contact hypersensitivity (CHS) mice in vivo and ovalbumin (OVA)-immunized BALB/c mice ex vivo as represented model of T-helper (Th) 2-induced allergy. Materials and methods: BALB/c mice were administered 250mg/kg body weight (BW) of fenugreek extract for 7 days after sensitization and challenge treatment with 2–5% TMA. Ear thickness were noted, and the infiltration of eosinophils and mast cells was investigated by hematoxylin and eosin (H&E) and toluidine blue (TB) staining. The supernatants from homogenized ear and splenocytes were used for cytokine determination using ELISA. In addition, splenocytes from OVA-immunized BALB/c mice were treated with fenugreek extract ex vivo. The levels of cytokines present in the supernatants were determined by ELISA. The mRNA expression of T-box transcription factor 21 gene (T-bet), GATA-binding protein 3 (GATA-3), interferon (IFN)-γ, and interleukin (IL)-4 were evaluated by real-time RT-PCR. Results: Fenugreek extract was found to reduce ear thickness as well as the infiltration of eosinophils and mast cells. In homogenized ear, the production of IL-4, IL-5, IL-13, and IL-1β was suppressed. To determine the mechanism by which fenugreek extract inhibits allergic skin inflammation, detailed studies were conducted revealing that fenugreek extract prevented differentiation into Th2 cells in the splenocytes of OVA-induced allergic mice, resulting from suppressing the secretion of IL-4 and mRNA expression of GATA-3, an IL-4 transcription factor. In earlier phase, these extracts enhanced the secretion of IFN-γ, the mRNA expression of T-bet, an IFN-γ transcription factor, and the number of IFN-γ-producing CD4+ T cells. Conclusions: These results indicate that fenugreek extract cures Th2-induced allergic skin inflammation by enhancing Th1 differentiation. These data suggest that fenugreek extracts may prove to be an useful therapeutic agent on allergic inflammatory diseases as traditional use as well as Th2-mediated allergic response. [Copyright &y& Elsevier]

Abstract: Many biological molecules in the stored blood were involved in transfusion-related immunomodulation. One important effect was the differentiation bias of immune cells to Th2 type. In this study, we observed the immune regulation of extracellular ubiquitin accummulated in the plasma of whole blood on the differentiation of T help cells in vitro using ELISA and quantitative fluorescence real-time PCR with the help of LPS stimulated human peripheral blood mononuclear cells. We found extracellular ubiquitin promoted Th2 cytokine IL-4 production and Th2-inducing transcription factor STAT6 expression, but inhibited Th1 cytokine IFN-γ and Th1-inducing transcription factor T-bet, at the same time, proinflammation cytokine TNF-α was also inhibited. These findings probably contribute to the potent evidence that extracellular ubiquitin plays an indispensable role in the differentiation of T help cells which is crucial to the effects of transfusion-related immunomodulation. [Copyright &y& Elsevier]

Abstract: The objective of the present study was to evaluate the expression of T-box expressed in T cells (T-bet) and GATA binding protein 3 (GATA-3) in the eutopic endometrium from women with endometriosis. Endometrial tissues were collected from 20 women with laparoscopically confirmed endometriosis and 20 women without endometriosis. T-bet and GATA-3 expression was measured by quantitative real-time PCR (qPCR), immunohistochemistry and Western blot analysis. Eutopic endometrial tissues from patients with endometriosis expressed lower levels of T-bet mRNA and high levels of GATA-3 mRNA, leading to a significant lower T-bet/GATA-3 mRNA ratio (P <0.05). Western blot analysis showed that the T-bet/GATA-3 protein ratio in endometriosis group was also statistically lower than that in the control group (P <0.05). These results suggested that T-bet and GATA-3 may act as cytokine regulatory genes, and the Th2-specific transcription factor, GATA-3, probably plays an essential role in the immune response and the development of endometriosis. [Copyright &y& Elsevier]

IL-4 produced by Th2 cells can block cytokine production by Th1 cells, and Th1 IFN-γ is known to counterregulate Th2 immune response, inhibiting allergic eosinophilia. As intrauterine undernutrition can attenuate lung inflammation, we investigated the influence of intrauterine undernourishment on the Th1/Th2 cytokine balance and allergic lung inflammation. Intrauterine undernourished offspring were obtained from dams fed 50% of the nourished diet of their counterparts and were immunized at 9 weeks of age. We evaluated the cell counts and cytokine protein expression in the bronchoalveolar lavage, mucus production and collagen deposition, and cytokine gene expression and transcription factors in lung tissue 21 days after ovalbumin immunization. Intrauterine undernourishment significantly reduced inflammatory cell airway infiltration, mucus secretion and collagen deposition, in rats immunized and challenged. Intrauterine undernourished rats also exhibited an altered cytokine expression profile, including higher TNF-α and IL-1β expression and lower IL-6 expression than well-nourished rats following immunization and challenge. Furthermore, the intrauterine undernourished group showed reduced ratios of the IL-4/IFN-γ and the transcription factors GATA-3/T-Bet after immunization and challenge. We suggest that the attenuated allergic lung inflammation observed in intrauterine undernourished rats is related to an altered Th1/Th2 cytokine balance resulting from a reduced GATA-3/T-bet ratio. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the effect of morphine on CD4-positive T cells differentiation and the transcriptional factors induced by phorbol myristate acetate (PMA) and ionomycin. CD4-positive lymphocytes separated from healthy volunteers were incubated by PMA (25 ng/ml) + ionomycin (1 μg/ml) with or without the presence of morphine, ketamine, or naloxone. Th subsets, supernatant cytokines, and transcriptional factors were detected 4 h later. Th1 and Th2 cells, levels of INF-γ, IL-2, IL-4 and the activities of T-bet and GATA3 were significantly increased after incubation with PMA and ionomycin. However, the number of Th1 cells, Th1/ Th2, the levels of INF-γ and INF-γ/IL-4, and the activities and protein levels of T-bet and GATA3 were decreased after incubation with PMA and ionomycin in the presence of morphine. Naloxone can abolish morphine's suppressive effect on Th cell differentiation. Morphine has a negative effect on Th cell balance induced by PMA and ionomycin, the mechanism is related to T-bet and GATA3. [ABSTRACT FROM AUTHOR]

Abstract: T-bet, a Th1-specific T-box transcription factor, regulates Th1 development by inducing endogenous Th1 cytokines and IFN-γ. This study was conducted to determine if T-bet knockout mice exhibit resistance to stress-induced development of depression-like behaviors. The T-bet knockout mice significantly reduced depressive-like behaviors provoked by repeated restraint stress in an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST). Moreover, stress-induced elevations of the pro-inflammatory cytokines were attenuated in T-bet deficient group. These results suggest that T-bet directly mediated stress-induced depression. Therefore, understanding T-bet function during stress represents an additional treatment strategy for depression. [Copyright &y& Elsevier]

Although recent reports suggest a possible role for an imbalance in Th1 and Th2 proinflammatory cytokines in the development and progression of glomerulonephritis, there is little information on Th1 or Th2 predominance in Henoch-Schönlein purpura nephritis (HSPN). Since T-bet and GATA-3 are transcriptional factors that regulate the differentiation of helper T lymphocytes into Th1 and Th2, we examined the relative mRNA expression of T-bet and GATA-3 in the urinary sediment of children with proteinuric HSPN by real-time quantitative PCR. Eight consecutive patients with proteinuric HSPN (4 with grade IIIa and 4 with grade IIIb according to the International Study of Kidney Disease in Children criteria) and 20 healthy subjects were enrolled in this study. The relative expression level of T-bet was significantly higher in the urinary sediment of patients with HSPN at presentation than in that of the healthy controls ( p = 0.021), while the relative expression of GATA-3 was significantly lower in the urinary sediment of patients than in that of controls ( p = 0.002). Urinary mRNA expression of T-bet correlated with the urinary protein/creatinine ratio ( r = 0.608, p = 0.013), and correlated inversely with serum level of total protein ( r = −0.574, p = 0.020). Moreover, a significantly increased intensity of T-bet immunostaining was observed in the glomeruli in the biopsy specimen of all study patients. All patients received immunosuppressive therapy. Repeat measurements of urinary mRNA expression of T-bet and GATA-3 after treatment revealed that the expression of T-bet in patients had significantly decreased relative to the baseline ( p = 0.003), while the expression of GATA-3 remained static. In a patient subjected to a post-treatment renal biopsy, the increased intensity of immunostaining of T-bet had clearly diminished following immunosuppressive treatment, in accordance with a significant decrease in urinary mRNA expression of T-bet. These observations suggest that patients with proteinuric HSPN demonstrate increased T-bet and depressed GATA-3 expression in the urinary sediment, indicating a possible shift in Th1/Th2 balance towards Th1 predominance. [ABSTRACT FROM AUTHOR]

Aim: A new subset of CD4+ T cells, Th17, has been recently discovered independent from Th1/Th2 paradigm. The aim of this study was to investigate the effects of nonsurgical periodontal therapy on the expression of Th17/Th1/Th2 cytokines and transcription factors, and Th17 cell vibration in Chinese chronic periodontitis patients. Materials and methods: The levels of Th17/Th1/Th2 cytokines (IL-17, IL-21/IFN-γ/ IL-4) in gingival crevicular fluid from 30 chronic periodontitis patients before and after treatment were determined by ELISA. The expression of transcription factors (RORC, T-bet and GATA-3) in peripheral blood was measured by real-time PCR, and the levels of Th17 cells in CD41 T cells were determined by flow cytometry. Results: After treatment, the levels of IL-17 and IL-21were down-regulated (P<0.05), and IL-4 was increased (P<0.05), but there were no differences in the level of IFN-γ (P<0.05). Correspondingly, the expression of RORC was decreased 1.99-fold (P<0.05), and GATA-3 was increased 1.76-fold (P<0.05). However, there were no differences in the level of T-bet (P>0.05). Moreover, the quantity of Th17 cells in peripheral blood was decreased (P<0.05), especially IL-17+IFN-γ+ subgroup. Conclusions: These results suggest that Th17 cells play a destructive role in the immune balance of periodontitis, and the effect of Th1 cells is not significant, while Th2 cells have a protective effect. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8 T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8pSTAT1, CD8T-bet T cells and CD14pSTAT1, CD14T-bet cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8pSTAT1, CD8T-bet and CD14pSTAT1 cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8 T cells, may favour FSHD progression by promoting active phases of muscle inflammation. [ABSTRACT FROM AUTHOR]

Background: Following antigen recognition, naive T helper (Th; CD4+) cells can differentiate toward one of several effector lineages such as Th1 and Th2; each expressing distinctive transcriptional profiles of cytokine genes. These cytokines eventually instruct the strategy of the immune response. In our search for factors that propagate the transcriptional programs of differentiated Th cells, we previously found that Polycomb group (PcG) proteins, which are known as epigenetic regulators that maintain repressive chromatin states, bind differentially the signature cytokine genes. Unexpectedly, their binding to the Ifng (Interferon-g) in Th1 cells and Il4 (Interleukin-4) in Th2 cells, was correlated with transcriptional activation. Therefore, in this study we aimed to determine the functional role of PcG proteins in the regulation of the expression of the signature cytokine genes. Methods: PcG proteins were knocked down in primary and established murine Th cells using transduction of lentiviruses encoding short hairpin RNAs (shRNAs) directed to Mel-18, Ezh2, Eed and Ring1A, representative of two different PcG complexes. The chromatin structure and the binding activity of PcG proteins and transcription factors at the Ifng promoter were assessed by chromatin immunoprecipitation (ChIP) assays. Results: Downregulation of PcG proteins was consistent with their function as positive regulators of the signature cytokine genes in primary and established Th1 and Th2 cells. Moreover, the PcG protein Mel-18 was necessary to recruit the Th1-lineage specifying transcription factor T-bet, and the T cell receptor (TCR)-inducible transcription factor NFAT1 to the Ifng promoter in Th1 cells. Nevertheless, our results suggest that PcG proteins can function also as conventional transcriptional repressors in Th cells of their known target the Hoxa7 gene. Conclusions: Our data support a model whereby the non-differentially expressed PcG proteins are recruited in a Th-lineage specific manner to their target genes to enforce the maintenance of specific transcriptional programs as transcriptional repressors or activators. Although our results suggest a direct effect of PcG proteins in the regulation of cytokine gene expression, indirect functions cannot be excluded. [ABSTRACT FROM AUTHOR]

Current research suggests that a number of newly identified T-helper cell subsets retain a degree of context-dependent plasticity in their signature cytokine expression patterns. To understand this process, a major challenge is to determine the molecular mechanisms by which lineage-defining transcription factors regulate gene expression profiles in T-helper cells. This mechanistic information will aid in our interpretation of whether a T-helper cell state that expresses or retains the capacity to re-express a combination of lineage-defining transcription factors will have a stable or more flexible gene expression profile. Studies examining the developmental T-box transcription factor T-bet demonstrate the powerful information that is gained from combining in vivo analysis with basic biochemical and molecular mechanism approaches. Significantly, T-bet's ability to physically recruit epigenetic modifying complexes, in particular a Jmjd3 H3K27-demethylase and a Set7/9 H3K4-methyltransferase complex, to its target genes allows T-bet to effectively reverse and establish new epigenetic states. This observation suggests that until T-bet is permanently extinguished, T-helper cells will retain some plasticity toward a T-helper 1-like program. Therefore, insight into the complexity of T-helper cell commitment decisions will be aided by determining the molecular mechanisms for lineage-defining transcription factors. [ABSTRACT FROM AUTHOR]

Abstract: We studied the effect of one-year interferon (IFN)-beta treatment on the in vivo mRNA expression of IFN-γ, interleukin (IL)-17, T-bet and RoR-γt, on peripheral blood mononuclear cells (PBMC) from 36 multiple sclerosis (MS) patients. In the total MS group, IFN-beta induced decrease in mRNA levels of IFN-γ and T-bet (p <0.0001), while the levels of IL-17 and RoR-γt remained similar. In both responders and non-responders, IFN-beta induced significant decrease of IFN-γ (p <0.0001 and p =0.011, respectively), while decrease in T-bet was detected only in responders (p <0.0001). Higher pre-treatment T-bet allowed prediction of the clinical response in the first year (β =0.601, p =0.036). Our preliminary findings suggest that T-bet expression might be a potential prognostic marker of treatment response to IFN-beta in MS. [Copyright &y& Elsevier]

Abstract: In order to analyze the effect of vitamin E on Th1 and Th2 cytokine production, porcine peripheral blood mononuclear cells (PBMC) were isolated from healthy pigs (n =8) and cultured with either 0, 10, 50, or 100μM of vitamin E (α-tocopherol). PBMC were stimulated with PHA for either, 24h to determine: (a) the concentration of tocopherol incorporated into the cell membrane, (b) cytokine production and (c) Th1 and Th2 regulators gene expression; or 72h to determine the proliferation of PBMC. Vitamin E was incorporated into the PBMC in a dose dependent manner, giving as a result a high proliferation of cells irrespective of the dose of vitamin E used. Regarding cytokine production, vitamin E consistently decreases the mRNA expression and the percentage of cells producing IL-10. Vitamin E did not influence the production of IFN-γ but the lowest level of vitamin E (10μM) was sufficient to maximally increase the proportion of cells producing IL-2, to diminish IL-4, and discreetly increase the mRNA expression of TBX21 vs. GATA3. In conclusion, our results revealed that vitamin E is able to suppress IL-10 production and to influence the production of IL-2, IL-4, and maybe TBX21. Vitamin E clearly has immunomodulatory effects, though further work in vivo to determine the physiological nature of these effects is warranted. [Copyright &y& Elsevier]

Abstract: Sinomenine has been used to treat autoimmune diseases for centuries. However, the mechanism underlying its therapeutic effects remains unknown. Increasing recognition of the importance of the Th1/Th2 imbalance in nephritis has raised the questions of whether there is a Th1/Th2 imbalance in patients with mesangial proliferative nephritis (MsPGN) and whether sinomenine can modulate the Th1/Th2 imbalance. In this study, 25 MsPGN patients were treated with sinomenine and followed for 3 months. The expression of T-bet and GATA-3 mRNA in peripheral blood mononuclear cells (PBMCs) and the serum levels of interferon-γ (IFN-γ), interleukin (IL)-4, and IL-10 were studied at month 0, month 1, and month 3. The intra-renal expression of T-bet and GATA-3 was studied via immunohistochemistry. Results reveal that PBMCs from MsPGN patients expressed high levels of T-bet mRNA and low levels of GATA-3 mRNA, and the T-bet/GATA-3 ratio in MsPGN patients was significantly higher than that in healthy donors. Meanwhile, MsPGN patients were found to have simultaneously elevated IFN-γ values and decreased IL-10 values. Immunohistochemistry revealed increased T-bet and decreased GATA-3 expression in renal tissues from MsPGN patients. Moreover, sinomenine was found to cause a decrease in T-bet mRNA expression, resulting in a drop in the T-bet/GATA-3 ratio. Sinomenine was also found to elicit a decrease in the serum levels of IFN-γ. These results suggest that a shift toward the Th1 pathway of Th cell activation occurs in MsPGN patients, and that sinomenine has the potential to counter this shift in the Th1/Th2 balance and thereby produce therapeutic effects. [Copyright &y& Elsevier]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is considered an auto-immune disorder. We evaluated expression of pSTAT1, T-bet, and pSTAT3 in circulating T-cells, B-cells, and monocytes and spontaneous production of interleukin-17 (IL17), interferon-gamma (IFNγ), and interleukin-10 (IL10) by peripheral blood mononuclear cells (PBMCs) from 14 active CIDP patients compared with 6 patients with long-lasting remission and 20 controls. Active disease patients showed higher pSTAT1, T-bet, and pSTAT3 in CD4+ T-cells than controls (p < 0.001, p = 0.0002, p = 0.0097, respectively) and remission patients (p < 0.001, p = 0.0036, p = 0.0008, respectively). pSTAT1, T-bet, and pSTAT3 were also higher in monocytes from active CIDP patients than controls (p = 0.0011, p = 0.0041, p = 0.0413, respectively) and remission patients (p = 0.0073, p = 0.0274, p = 0.0251, respectively). Moreover in CD8+ T-cells, pSTAT3 expression was higher in active CIDP patients than in remission patients (p = 0.0345) and in controls (p = 0.0023). IL17 and IFNγ production were significantly higher in active CIDP patients than in controls (p < 0.0395, p = 0.0010, respectively); IFNγ levels were higher also in remission CIDP patients (p = 0.0073). IL10 levels were higher in active phase patients than in controls (p = 0.0334). Our data suggest that pSTAT1, T-bet, and pSTAT3 can be considered putative markers of disease activity and potential targets for specific therapies. [ABSTRACT FROM AUTHOR]

Abstract: The application of immunostimulants may be a cost-effective practice in production of delicate and fragile fish fry since it may confer disease resistance. Bath administration to fish fry is considered an ideal delivery route for mass manipulation since there is no need for individual handling. In the current study, rainbow trout fry were bathed with three different immunostimulants: Plasmid DNA, lactoferrin and β-glucan at two different doses (0.1 μM and 1.0 μM) for 45 min, four times with an interval of 1 week. Ten fish per treatment group were sampled, and RNA of pooled tissues consisting of eye, tongue, skin, gill, thymus, spleen, head kidney, liver, small and large intestine were isolated from the fish obtained at first, second and fourth bathing (24 and 72 h post-bathing). Before cDNA transcription, two parallel samples were pooled giving a total of 5 parallels in each treatment group. Results showed that plasmid DNA and lactoferrin as well as β-glucan treated fish possessed higher gene expression with regard to the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and the anti-inflammatory cytokines IL-10 and TGF-β after the first bathing, especially 24 h post-bathing in the high-dose groups. This indicates that bath delivery of immunostimulants can induce pro-inflammatory responses. No significant changes of the pro-inflammatory cytokine IL-17A transcripts, compared to the respective controls, were observed. Gene expression levels in the immunostimulated fish after the fourth bathing did not show significant differences compared to controls. [Copyright &y& Elsevier]

Abstract: Naturally occurring phenolic compounds, such as chavicol analogues, have been shown to have potent antioxidant and anti-inflammatory activities. We have previously isolated two chavicol acetate analogues, acetoxychavicol acetate (ACA) and hydroxychavicol acetate (HCA) from the rhizomes of Alpinia galanga. Although the function of ACA has been studied in many systems, the function of HCA has yet to be systemically examined. In this study, we have comparably examined the functions of ACA and HCA on the cytokine production in Th cells. ACA exhibited potent antioxidant activity and increased cell apoptosis; therefore, cytokine production by Th cells was diminished. Although HCA had neither antioxidant activity nor pro-apoptotic function, it was shown to increase IL-2 production and attenuate IFNγ expression in Th cells. In addition, we demonstrated that HCA suppressed T-bet expression, which is responsible for IL-2 suppression and IFNγ induction in Th cells and inhibited T-bet-mediated Th1 cell differentiation. Therefore, we suggest that HCA may be beneficial as therapeutics for treating inflammatory immune disorders caused by extravagant activation of Th1-mediated immune responses. [Copyright &y& Elsevier]

The molecular interaction between hormonal and cytokine signals is crucial for providing specificity to their actions and represents a key step for understanding, at the molecular level, the ultimate response of physiological neuroendocrine-immune interactions. In this article we will describe new insights into the mechanisms underlying glucocorticoid-mediated anti-inflammatory action, focused on the regulation of immune–cytokine pathways. There are different levels of interaction between intracellular signals elicited by glucocorticoids and cytokines, with the final outcome being regulation of gene expression. One such interaction involves the molecular cross-talk between the activated glucocorticoid receptor (GR) and transcription factors implicated in the regulation of cytokine synthesis and function. This interaction results in the regulation of gene transcription, as we will illustrate with the helper T (Th)1 and Th2 transcription factors T-bet and GATA-3, respectively, implicated in the outcome of specific adaptive immune responses. A further level of mutual regulation is the posttranslational modification of GR by the ubiquitin–proteasome and sumoylation systems. These posttranslational modifications regulate GR activity and will be discussed for the small ubiquitin-related modifier (SUMO) pathway and its enhancer RWD RING finger-containing proteins, WD-repeat-containing proteins, and yeast DEAD (DEXD)-like helicases-containing sumoylation enhancer (RSUME). The impact of posttranslational modifications on inflammatory pathways, such as nuclear factor-κβ and regulated cytokines, will also be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Neem leaf glycoprotein (NLGP)–mediated immune activation and associated immune polarization was studied. NLGP–induced activation is reflected in upregulation of early activation marker CD69 on lymphocytes, monocytes, and dendritic cells. Activation is also denoted by CD45RO enhancement, with a decrease in CD45RA phenotype and CD62L (L-selectin). NLGP-activated T cells secrete greater amount of signature T-helper (Th)1 cytokines interferon-γ and a lower amount of the Th2 cytokine interleukin (IL)–4. Similar type 1 directiveness is also observed in antigen-presenting monocytes and dendritic cells by upregulation of IL-12, tumor necrosis factor –α and downregulation of IL-10. Creation of the type 1 microenvironment is also assisted by NLGP-induced downregulation of FoxP3+ T-Reg cells. A type 1–specific transcription factor, T-bet, is upregulated in circulating immune cells after their stimulation with NLGP. In the creation of type 1 immune network, increased phosphorylation of STAT1 and STAT4 with decreased phosphorylation of STAT3 might have significance. We conclude that NLGP may be effective in maintaining normal immune homeostasis by upregulating type 1 response in immunosuppressed hosts, which may have significant role in the induction of host protective antitumor functions. [Copyright &y& Elsevier]

Three major subsets of antigen-experienced T cells have been identified based on surface markers and distinct functional properties: short-lived effector T cells, central memory T cells and effector memory T cells. The precise relationship among these subsets and their mode of differentiation are still controversial. Recent studies, however, have provided compelling evidence for an early delineation of the effector versus memory T-cell fates regulated through specific transcription factors. Cytokines have long been recognized as being important for the shaping of a T-cell response and for the maintenance of memory T cells. The observation that short-lived effector and memory T cells, as well as their precursors, express distinct levels of IL7R has provided an important tool to examine the role that cytokines play in the programming of T-cell differentiation pathways and of the transcriptional regulators that guide these processes. IL2 and IL12 in particular have been shown to provide the signals that induce or repress transcription factors, such as T-bet, Eomes and Blimp-1, all of which are crucial in the differentiation and homoeostasis of effector and memory T cells. The coordinated differentiation of a heterogeneous population of antigen-specific T cells early during an immune response is essential for the effective eradication of pathogens and the long-term protection against reinfection. Thus, understanding the signals and transcriptional programmes in T-cell differentiation is a key to successful manipulation of T-cell responses during vaccination.Immunology and Cell Biology (2008) 86, 325–332; doi:10.1038/icb.2008.16; published online 25 March 2008 [ABSTRACT FROM AUTHOR]

Recent studies have suggested that gene expression studies using urinary sediment might be a non-invasive approach to assessing activity and pathogenesis in glomerulonephritis. However, little information is available regarding the mRNA expression patterns of functional molecules, such as T-bet, GATA-3, FOXP3, and retinoic acid-inducible gene-I (RIG-I), in urinary sediment, from patients with immunocomplex-mediated glomerulonephritis. Fourteen lupus nephritis (LN) patients, 13 IgA nephropathy (IgAN) patients, and 12 healthy controls were enrolled in the study. The mRNA expressions of T-bet, GATA-3, FOXP3 and RIG-I in urinary sediment were measured using real time quantitative polymerase chain reaction. We also studied the expression of RIG-I in kidney tissue specimens obtained from LN and IgAN patients. Significant differences in the expression patterns of GATA-3, FOXP3 and RIG-I, and marginal differences in T-bet expression, were observed between the three study groups. Immunofluorescent staining for RIG-I was observed in the tissue specimens from the LN patients, but not in those from the IgAN patients. The mRNA expression patterns of T-bet, GATA-3, FOXP3 and RIG-I in urinary sediment differ according to diagnostic category. These results suggest that the measurement of these target gene expressions might be a useful, non-invasive method for clinical monitoring and studying of pathogenesis in glomerulonephritis. [ABSTRACT FROM AUTHOR]

Endometrial cytokine expression is poorly understood. T-Bet and GATA-3 regulate cytokine expression in T-lymphocytes. Previous work has demonstrated expression of T-Bet in human endometrium. Changes in human endometrial T-Bet and GATA-3 mRNA and protein expression during the normal menstrual cycle were characterized. Human endometrium from each phase of the menstrual cycle underwent real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry to examine expression and localization. T-Bet and GATA-3 mRNA were increased in the late secretary phase. Progesterone receptor (PR) mRNA was increased during the proliferative and early secretory phases. T-Bet and GATA-3 proteins localized cytoplasmically in the late secretory phase. PR protein displayed nuclear localization and maximal immunostaining during the early secretory phase. T-Bet and GATA-3 are expressed in endometrial epithelium cyclically during the menstrual cycle. T-Bet and GA TA-3 are both upregulated during the late secretory phase and in the same cell types. The expression patterns of T-Bet and GATA-3 oppose PR, suggesting antagonistic function and/or regulation between PR and T-Bet/GATA-3. [ABSTRACT FROM AUTHOR]

The 5′-phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient I cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Thi-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8+ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in I cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity. [ABSTRACT FROM AUTHOR]

Highly sophisticated mechanisms confer upon the immune system the capacity to respond with a certain degree of autonomy. However, the final outcome of an adaptative immune response depends on the interaction with other systems of the organism. The immune–neuroendocrine systems have an intimate cross-communication, making possible a satisfactory response to environmental changes. Part of this interaction occurs through cytokines and steroid hormones. The last step of this crosstalk is at the molecular level. In this article we will focus on the physical and functional interrelationship between cytokine signaling pathway–activated transcription factors (TFs) and steroid receptors in different cell models, where the signals triggered by cytokines and steroid hormones have major roles: (1) the ligand-dependent-activated glucocorticoid receptor (GR) influence the genetic program that specifies lineage commitment in T helper (Th) cell differentiation. How posttranslational modifications of several TFs as well as nuclear hormone receptors could be implicated in the molecular crosstalk between the immune–neuroendocrine messengers is discussed. (2) glucocorticoid (GC) antagonism on the TCR-induced T cell apoptosis. (3) estrogen receptor/TGF-β family proteins molecular interaction implicated on pituitary prolactinomas pathogenesis. The functional crosstalk at the molecular level between immune and steroids signals is essential to determine an integrative response to both mediators (which in the last instance results in a new gene activation/repression profile) and constitutes the ultimate integrative level of interaction between the immune and neuroendocrine systems. [ABSTRACT FROM AUTHOR]

Background: To investigate the functional role of protease activated receptor (PAR) -2 in T lymphocytes, we analyzed TCR-mediated inflammatory cytokine production using PAR-2 deficient (KO) and wild type (WT) mice. Methods: Production of serum IgE and cytokines by spleen CD4+ T cells was determined in OVA-sensitized and OVA-challenged mice of PAR-2 KO in contrast to WT mice. Phosphorylation of JNK1 and 2 was determined by Western blotting. Results: A reduction in serum levels of IgE and IL-4 production by splenic CD4+ T cells from OVA-sensitized and OVA-challenged KO mice compared to WT mice was observed. By contrast, IFN-γ production was upregulated after antigen stimulation in KO mice. Anti-CD3-mediated phosphorylation of JNK1 was upregulated in splenic CD4+ T cells from KO mice compared to WT mice. Conclusions: PAR-2 participates in the regulation of T cell cytokine production that may be caused by modulation of JNK1 phosphorylation. [ABSTRACT FROM AUTHOR]