Regulatory T (Treg) cells maintain immune homeostasis by preventing abnormal or excessive immune responses. Histone deacetylase 6 (HDAC6) regulates expression of Foxp3, and thus, Treg cell ...differentiation; however, its role in Treg cell differentiation is unclear and somewhat controversial. Here, we investigated the role of HDAC6 in TGF-β-induced murine Treg cells. HDAC6 expression was higher in Treg cells than in other T helper cell subsets. Pharmacological inhibitors of HDAC6 selectively inhibited Treg cell differentiation and suppressive function. A specific HDAC6 inhibitor induced changes in global gene expression by Treg cells. Of these changes, genes related to cell division were prominently affected. In summary, HDAC6 plays an important role in TGF-β-induced murine Treg cell differentiation by regulating cell proliferation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Regulatory T (Treg) cells are a CD4 T-cell subset with an important role in immune tolerance; however, the mechanisms underlying Treg cell differentiation and function are incompletely understood. ...Here, we show that NFIL3/E4BP4, a transcription factor, plays a key role in Treg cell differentiation and function. Microarray analysis showed that Treg cells had lower Nfil3 expression than all other CD4 T-cell subsets. Overexpression of Nfil3 in Treg cells led to diminished expression of Foxp3 and other signature Treg genes, including Il2ra, Icos, Tnfrsf18, and Ctla4. Furthermore, Nfil3-overexpressing Treg cells exhibited impaired immunosuppressive activity in vitro and in vivo. We discovered that NFIL3 directly binds to and negatively regulates the expression of Foxp3. In addition, bisulfite sequencing revealed that NFIL3 induces methylation at Foxp3 locus regulatory CpG sites, which contributes to the control of Treg cell stability. Together, these data indicate that NFIL3 impairs Treg cell function through the downregulation of Foxp3 expression.
To find a new and safe alternative to conventional insecticides, we evaluated the fumigant toxicity of eight Lamiaceae essential oils and their constituents against the adult rice weevil Sitophilus ...oryzae. Of the eight species tested, hyssop (Hyssopus offcinalis), majoram (Origanum majorana), and Thymus zygis essential oils showed strong fumigant toxicity against S. oryzae adults at 25 mg/L air concentration. Constituents of active essential oils were analyzed by gas chromatography coupled to flame ionization detector (FID) and gas chromatography-mass spectrometry. A total of 13, 15, and 17 compounds were identified from hyssop, majoram, and Thymus zygis essential oils, respectively. Pinocamphone and isopinocamphone were isolated by open column chromatography. Among the test compounds, pinocamphone and isopinocamphone showed the strongest fumigant toxicity against S. oryzae. Sabinene hydrate, linalool, α-terpineol, and terpinen-4-ol exhibited 100% fumigant toxicity against S. oryzae at 3.9 mg/L air concentration. The measured toxicity of the artificial blends of the constituents identified in hyssop, majoram, and Thymus zygis oils indicated that isopinocamphone, terpine-4-ol, and linalool were major contributors to the fumigant toxicity of the artificial blend, respectively.
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•We detected cysteine-induced H2S in saliva using a colorimetric H2S assay.•The salivary H2S was varied on the cysteine concentration, time, and bacterial composition.•A silver ...nanoprism-coated H2S sensing paper was used to quantitatively analyze salivary H2S.•Cysteine-induced salivary H2S was positively correlated with the DNA copy number of Pg.•Cysteine-induced salivary H2S can be used to evaluate the H2S producing capability of oral bacteria.
The cysteine challenge test can be used to evaluate the ability of oral bacteria to produce malodor. But it involves administration of high concentrations of cysteine directly into the mouth, together with requiring special and expensive instruments. In this study, we detected cysteine-induced hydrogen sulfide (H2S) in saliva using two colorimetric H2S assays: a microplate cover-based assay and a silver nanoprism (Ag NPR)-coated paper-based assay. Based on the results of the microplate cover-based H2S sensing assay, salivary H2S varied with cysteine concentration, treatment time, and bacterial composition. The Ag NPR-coated H2S sensing paper assay was used to quantitatively analyze cysteine-induced H2S concentrations in 21 saliva samples treated with 20 mM cysteine for 3 min. As a result, the cysteine-induced salivary H2S level was within a range from 1.43 to 3.60 μM. And it was positively correlated with the DNA copy number of Porphyromonas gingivalis in the saliva. Therefore, we suggest that cysteine-induced salivary H2S be used as an alternative to the oral cysteine challenge test for evaluating the H2S-producing capability of oral bacteria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
T helper 17 (Th17) cells are a CD4
T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is ...suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific
deletion (
) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically,
deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression.
Regulatory T (T(reg)) cells are essential for maintenance of immune homeostasis. Foxp3 is the key transcription factor for T(reg)-cell differentiation and function; however, molecular mechanisms for ...its negative regulation are poorly understood. Here we show that YY1 expression is lower in T(reg) cells than T(conv) cells, and its overexpression causes a marked reduction of Foxp3 expression and abrogation of suppressive function of Treg cells. YY1 is increased in T(reg) cells under inflammatory conditions with concomitant decrease of suppressor activity in dextran sulfate-induced colitis model. YY1 inhibits Smad3/4 binding to and chromatin remodelling of the Foxp3 locus. In addition, YY1 interrupts Foxp3-dependent target gene expression by physically interacting with Foxp3 and by directly binding to the Foxp3 target genes. Thus, YY1 inhibits differentiation and function of T(reg) cells by blocking Foxp3.
The objective of this study was to investigate the influence of feeding frequency on a sow's reproductive performance and stress response during gestation. A total of twenty multiparous sows ...(Yorkshire × Landrace) were used in a completely randomized design based on their parity, body weight (BW), and backfat thickness (BFT), and the sows were allotted to two different feeding systems: 1) once daily feeding (OF) and 2) twice daily feeding (TF) in corn-soybean meal based diets. The gestation diet was formulated to contain 3,265 kcal of metabolizable energy (ME) / kg, 12.90% of crude protein (CP), and 0.75 % of total lysine. The lactation diet was formulated to contain 3,265 kcal of ME / kg, 16.80% of CP, and 1.08% of total lysine and provided ad libitum during lactation. In gestation, sow BFT and BF changes were not affected by feeding frequency, but higher BW and BW gain from day 35 to 90 and day 35 to 110 were observed in OF sow (
< 0.10). In lactation, feeding frequency did not influence on BW, BW gain, BFT, BF changes, average daily feed intake, and wean-to-estrus interval. Also, there were no differences in litter size, litter weight and piglet weight in lactating sows. OF sows had higher (
< 0.05;
< 0.10) protein, solid-not-fat, and total solid concentrations in colostrum compared to TF sows, while OF sows had a lower (
< 0.05) lactose concentration in colostrum compared to TF sows. Sows in OF showed significantly lower average daily water consumption (ADWC) from day 35 to 110 of gestation (
< 0.05). While there were no significant differences in stereotypic behaviors and salivary cortisol levels during gestation between treatments, the OF sows showed less time spending on the activity at day 105 (
< 0.05). In conclusion, reduced feeding frequency increased BW gain during gestation, decreased activation time, and changed the colostrum composition. This information may contribute to the understanding of the physiological and behavioral change of gestating sows by manipulating feeding frequency.
Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases owing to their immunosuppressive properties. In this study, we aimed to identify the effect of ...interferon (IFN)-γ priming on immunomodulation by MSCs and elucidate the possible mechanism underlying their properties for the clinical treatment of allogeneic conflicts. Infusion of MSCs primed with IFN-γ significantly reduced the symptoms of graft-versus-host disease (GVHD) in NOD-SCID mice, thereby increasing survival rate when compared with naïve MSC-infused mice. However, infusion of IFN-γ-primed MSCs in which indoleamine 2,3-dioxygenase (IDO) was downregulated did not elicit this effect. The IDO gene was expressed in MSCs via the IFN-γ-Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) pathway, and the infusion of IDO-over-expressing MSCs increased survival rate in an in vivo GVHD model, similar to infusion of IFN-γ-primed MSCs. These data indicate that IFN-γ production by activated T-cells is correlated with the induction of IDO expression in MSCs via the IFN-γ-JAK-STAT1 pathway, which in turn results in the suppression of T-cell proliferation. Our findings also suggest that cell therapy based on MSCs primed with IFN-γ can be used for the clinical treatment of allogeneic conflicts, including GVHD.
•IFN-γ priming enhances the immunosuppressive properties of human MSCs in in vitro and in vivo models.•IFN-γ priming induces IDO expression in MSCs via the JAK/STAT1 signaling pathway, but TLR3 activation does not.•Cell therapy using MSCs primed with IFN-γ could be highly effective in treating allogeneic diseases, including GVHD.
It is necessary to improve the function of mesenchymal stem cells (MSCs) to maximize their treatment potential beyond what is currently achieved in cell therapy studies using naïve heterogeneous MSCs. The preclinical study of a candidate cell therapy based on MSCs primed with interferon-γ as reported in this study, could lay the foundation for the use of cell therapy for the treatment of graft-versus-host disease (GVHD), and is very important for the initiation of clinical trials. Our findings also suggest that cell therapy based on functionally improved MSCs could be used for the clinical treatment of allogeneic conflicts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Th9 cells preferentially produce IL-9 and participate in allergic responses and asthma. Differentiation of Th9 cells is induced by IL-4 and TGF-β, and then the cells are amplified by OX40 signals. ...The transcription factors PU.1, IRF4, and BATF are required for Th9 differentiation. BATF3 is an AP-1 family transcription factor that is highly homologous to BATF; however, its role in Th9 cells is poorly defined. Here, we show that OX40 signaling induced the expression of Batf3 and that its overexpression in the presence or absence of OX40 signaling increased the expression of IL-9 in Th9 cells. BATF3 physically interacted with IRF4 and was bound to the Il9 locus. A transient reporter assay revealed that the BATF3-IRF4 complex induced Il9 promoter activity. BATF3 rescued Il9 expression and restored the capacity to induce the airway inflammation in Batf KO Th9 cells. Thus, BATF3 itself is sufficient for the induction of Th9 cell differentiation and can substitute for BATF during Th9 cell differentiation.
The Th2 locus control region (LCR) has been shown to be important in efficient and coordinated cytokine gene regulation during Th2 cell differentiation. However, the molecular mechanism for this is ...poorly understood. To study the molecular mechanism of the Th2 LCR, we searched for proteins binding to it. We discovered that transcription factor YY1 bound to the LCR and the entire Th2 cytokine locus in a Th2-specific manner. Retroviral overexpression of YY1 induced Th2 cytokine expression. CD4-specific knockdown of YY1 in mice caused marked reduction in Th2 cytokine expression, repressed chromatin remodeling, decreased intrachromosomal interactions, and resistance in an animal model of asthma. YY1 physically associated with GATA-binding protein-3 (GATA3) and is required for GATA3 binding to the locus. YY1 bound to the regulatory elements in the locus before GATA3 binding. Thus, YY1 cooperates with GATA3 and is required for regulation of the Th2 cytokine locus and Th2 cell differentiation.
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