Inhibition of interleukin-13 gene expression by triptolide in activated T lymphocytes
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Triptolide, a type of diterpenoid, is the active compound of Tripterygium wilfordii; it plays roles in anti-inflammatory and immune response regulation. Our objective was to investigate the mechanism of the inhibitory effect of triptolide on interleukin-13 (IL-13) gene expression in activated T lymphocytes. Understanding the molecular mechanism by which triptolide exerts a therapeutic function may be useful in developing a pharmaceutical treatment for asthma.Peripheral blood mononuclear cells (PBMC) and Hut-78 cells were stimulated with anti-CD3/CD28 with or without co-incubation with triptolide. The alteration of IL-13 messenger RNA (mRNA), expression and protein level were analysed using real-time reverse transcription polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay, respectively. The intracellular distribution profile of transcription factor GATA3 and nuclear factor of activated T cells (NFAT1) were analysed by Western blotting. The binding rates of GATA3 and NFAT1 to the promoter sequence of IL-13 were analysed by chromatin immunoprecipitation (ChIP) PCR.In PBMC, the release of IL-13 was dependent on anti-CD3/CD28 stimulation. Its release could be inhibited by triptolide at the concentration of 500 nmol. In Hut-78 cells, IL-13 mRNA and protein expression were increased with anti-CD3/CD28 stimulation and significantly inhibited by incubation with 28 nmol triptolide. This concentration of triptolide also significantly inhibited the nuclear translocation of GATA3 and NFAT1 reducing the binding rate to the IL-13 gene promoter.Triptolide inhibits IL-13 gene transcription and protein expression by inhibiting GATA3 and NFAT1 nuclear translocation and their binding rates to the IL-13 gene promoter region.Keywords:
Triptolide
Interleukin 1β
Interleukin 15
Interleukin 11
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The effect of isoniazid on interleukin 2 production and interleukin 2-receptor expression by phytohemagglutinin-stimulated human T cells was investigated. High concentrations of the drug decreased interleukin 2 production while low doses (10(-5)-10(-6) M) produced a slight increase in interleukin 2 production. Isoniazid did not affect the expression of interleukin 2-receptors on the surface of T cells, except a slight decrease in cells exposed to high levels of the drug.
Receptor expression
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The use of human interleukin 4 (IL4) in the generation of tumoricidal effector cells derived from cancer patients undergoing either interleukin 2/lymphokine activated killer cells (IL2/LAK) therapy or tumor derived activated cell (TDAC) therapy was examined in the present study. Human IL4 alone did not generate LAK cells from patients undergoing IL2/LAK therapy when cultured in media containing 2% AB serum (five out of six patients). However, when the serum free medium, Aim V, was used, IL4 did generate LAK cells (eight out of nine patients), although not as cytotoxic as those activated with IL2. When cells were cultured in both IL2 and IL4 during the generation of LAK cells (3-7 days), better cell recoveries were frequently observed. The cytolytic activity of these cells against Daudi target cells was slightly reduced when compared to that response induced by IL2. This inhibition of LAK activity by IL4 was dose dependent with 1,000 U/ml IL4 producing maximal effects. This form of inhibition did not correlate with any phenotypic differences between those cells cultured in IL2 and those cells cultured in IL2 plus IL4. The IL4 mediated inhibition was also observed when the cells were cultured in Aim V medium which contains indomethacin. This inhibition induced by IL4 could not be overcome by using supra-optimal IL2. In addition to its effect during the generation of IL2 induced LAK cells, IL4 also appeared to reduce the cytolytic activity of pre-activated mature LAK cells. These results suggest that IL4 has a complex role in regulating the actions of LAK cells induced by lymphokines. When IL4 was used with IL2 during the first 5 weeks of growth of TDAC, an enhanced growth was observed when compared to the growth of TDAC when only one lymphokine was used. Besides the growth enhancement of TDAC, a better cytolytic response was observed when both lymphokines were used together. Thus, for the best growth of TDAC both IL2 and IL4 are required.
Lymphokine-activated killer cell
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Abstract Purified protein derivative reactive T cell lines were established under identical conditions with the exception that different lymphokines, namely interleukin (IL) 2 and IL 4 were employed as growth factors. IL 2 favored the development of T cell lines (LNC.2) which upon activation by concanavalin A (Con A) secreted predominantly lymphokines characteristic of T H 1 cells. By contrast, T cell lines established with the aid of IL4 as growth factor (LNC.4) produced mainly lymphokines representative of T H 2 cells. Apart from their pattern of lymphokine secretion LNC.2 and LNC.4 T cells were found to differ in their proliferative response to lymphokines and Con A. LNC.2 T cells proliferated only marginally in the presence of IL 4, Con A or a combination of Con A and IL 1. Furthermore, the IL 2‐dependent proliferation of LNC.2 T cells was slightly but significantly diminished by IL 4. In contrast, LNC.4 T cells showed a substantial IL 4‐induced proliferative response which was on the one hand synergistically enhanced by minimal amounts of IL 2 and, on the other hand, strongly inhibited by interferon‐γ. In addition, LNC.4 T cells displayed a strong proliferation when stimulated by low concentrations of Con A in the presence of IL 1 as co‐stimulator.
Interleukin 3
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Rhesus macaque
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Interleukin 1β
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Objective To study the effect of Interleukin-25 on expressing Th2 inflammatory factor in mouse asthma by nuocyte cells. Methods Nuocytes were collected from mouse spleen of OVA-induced asthma model by density gradient centrifugation. Samples were divided into 3 groups according to different intervention conditions:Interleukin-25 group; control group; anti-Interleukin-25 group. The expression of Interleukin-5 and Interleukin-13 proteins in nuocyte cells supernatant was detected by ELISA. The expression of Interleukin-5 and Interleukin-13 in nuocyte cells was detected by Western blot. The expression of Interleukin-5 and Interleukin-13 mRNA was detected by RT-PCR. The number of nuocyte cells was detected by flow cytometry. Results The expression of Interleukin-5 and Interleukin-13 protein and related gene in Interleukin-25 group was higer than that in the control group or anti-Interleukin-25 group( P 0. 05). The number of nuocyte cells in Interleukin-25 groupwas more than that in control group or anti-interleukin-25( P 0. 05). Conclusions Interleukin-25 can promote the expressing Interleukin-5 and Interleukin-13 in asthma by nuocyte cells and promote the occurrence and development of asthma.
Interleukin 19
Interleukin 1β
Interleukin 3
Interleukin 8
Interleukin 9
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Interleukin-2 has been reported to enhance the immune response in diseases characterised by defective cell mediated immunity. The effect of exogenous recombinant interleukin-2 was studied on the proliferative and cytotoxic responses of peripheral blood mononuclear cells from 39 patients with sarcoidosis and 14 healthy control subjects. The proliferative response to purified protein derivative was smaller in patients than in control subjects (p less than 0.001) whereas the response to 80 U interleukin-2 alone and to purified protein derivative and interleukin-2 did not differ significantly between the two groups. In addition, in eight patients but no control subjects tritiated thymidine incorporation induced by the combination of purified protein derivative and interleukin-2 was more than twice the sum of that induced by purified protein derivative and interleukin separately. Cytotoxic activity occurring spontaneously and induced by purified protein derivative and interleukin-2 in blood mononuclear cells was significantly less for patients with sarcoidosis than for control subjects (p less than 0.05 spontaneous, less than 0.001 purified protein derivative induced, less than 0.02 interleukin induced). Synergism between antigen and interleukin did not occur with respect to the cytotoxic response in either patients or controls. Defective interleukin-2 production may contribute to, but does not entirely explain, the functional abnormalities of peripheral blood lymphocytes from patients with sarcoidosis.
Cellular immunity
Purified protein derivative
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In an attempt to augment the generation of human cytotoxic effector cells for potential cancer therapy with interleukin 2 (IL2) and lymphokine-activated killer (LAK) cells, the effect of interleukin 4 (IL4) on LAK cell induction was studied. In normal human peripheral blood lymphocytes (PBL), IL4 does not induce LAK activity and inhibits LAK induction by IL2. However, since lymphocyte activation, such as with antigen or mitogen, can render them responsive to IL4, the ability of IL4 to induce LAK activity in lymphocytes preactivated in vivo or in vitro with IL2 was investigated. PBL obtained from 12 patients with advanced cancer 1 to 3 days after IL2 therapy and from eight healthy control subjects were cultured 4 to 5 days with or without IL4 and/or IL2 and then tested for LAK activity as assessed by lysis of Daudi in a 4-h 51Cr release assay. In normal PBL, IL4 failed to induce LAK activity and consistently inhibited LAK induction by a suboptimal concentration of IL2 (10 units/ml). By contrast, IL4 induced LAK activity in PBL from seven of twelve IL2-treated patients and augmented LAK induction by the suboptimal IL2 in PBL from five of twelve IL2-treated patients. With an optimal LAK-inducing concentration of IL2 (1000 units/ml), IL4 less consistently inhibited LAK induction in normal PBL and had a variable effect upon LAK induction in PBL from IL2-treated patients. IL4 induced LAK activity in PBL obtained from a cancer patient after, but not before, systemic IL2 therapy. Similarly, IL4 induced LAK activity in normal PBL only after they had been preincubated with IL2. Thus, IL4 induces LAK activity in lymphocytes preactivated by IL2 in vivo or in vitro. Fluorescence-activated cell sorting revealed that the LAK activity, whether induced by IL4 or by IL2, was mediated largely by non-T (CD5-) natural killer-like (CD56+) cells. The results suggest a regulatory relationship between IL2 and IL4 in the induction and/or maintenance of LAK activity, which might be exploited to augment the generation of cytotoxic cells for lymphokine-mediated immunotherapy of human cancer.
Lymphokine-activated killer cell
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