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T cell growth factor [keywords]
- Association of IL-2 Polymorphisms and IL-2 Serum Levels with Susceptibility to HBV-related Hepatocellular Carcinoma in a Chinese Zhuang population. [JOURNAL ARTICLE]
- Infect Genet Evol 2014 Aug 27.
Interleukin-2 (IL-2) is an immunoregulatory cytokine produced by T cells and plays an important role in antitumor immunity. Variations in the DNA sequence of the IL-2 gene may lead to altered cytokine production and/or activity, and thus modulate an individual's susceptibility to hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). To test this hypothesis, we investigated whether IL-2 gene polymorphisms and its serum levels are associated with HBV-related HCC in a Chinese population.The +114T/G and -384T/G polymorphisms in the IL-2 gene were examined in 115 cases of chronic hepatitis B (CHB), 67 cases of HBV-related liver cirrhosis (LC), 107 cases of HBV-related HCC, and 105 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. The serum IL-2 levels were measured by enzyme-linked immunosorbent assay (ELISA).We found that there were significant differences in the genotype and allele frequencies of the IL-2 gene +114T/G polymorphism between the HBV-related HCC patients and the healthy controls. The +114 TG and GG genotypes were associated with a significant increased HCC risk as compared with the TT genotype (OR = 1.988, 95% CI, 1.034-3.480, P = 0.009 for TG genotype, and OR = 1.975, 95% CI, 1.012-3.341, P = 0.013 for GG genotype, respectively). The +114 G allele was correlated with a significant increased HCC risk as compared with the T allele (OR = 1.423, 95% CI, 1.023 - 1.975, P = 0.031). In addition, we found significant decreased serum IL-2 in HBV-related HCC patients (288.6±177.1 ng/L) compared with healthy controls (238.2±136.7 ng/L) (t=2.32, P=0.021). Genotypes carrying the +114 G variant allele were associated with decreased serum IL-2 levels compared with the homozygous wild-type genotype in HBV-related HCC patients.The results suggested that the IL-2 +114T/G polymorphism may contribute to increased HBV-related HCC risk through regulating the serum IL-2 levels. Further large and well-designed studies in diverse ethnic populations are needed to confirm our results.
- Silver and fullerene nanoparticles' effect on interleukin-2-dependent proliferation of CD4 (+) T cells. [JOURNAL ARTICLE]
- Toxicol In Vitro 2014 Aug 26.
Immunotoxicity studies of nanoparticles on T cells addressed their effects on activation by T antigen receptor, but have neglected the regulation of proliferation by IL-2. In this study, the IL-2-dependent T lymphoblastoid WE17/10 cell line was used to compare silver (Ag-NPs) and fullerene (C60-NPs) nanoparticles' toxicity and evaluate whether these NPs could interfere with IL-2-dependent proliferation. Results have shown that Ag-NPs are more toxic, as they reduced cell viability at the highest concentration tested (100 μg/ml), while C60-NPs have shown good biocompatibility. Characterization of NP suspensions by dynamic light scattering measured large aggregates for C60-NPs, whereas Ag-NPs were relatively stable and well dispersed. This translated into a much larger uptake of Ag-NPs compared to C60-NPs, as measured by flow cytometry. Proliferation measurements by CFSE following 72h incubation have shown that Ag-NPs decrease cell proliferation and C60-NPs slightly increase proliferation. CD25 expression was unchanged following exposure to C60-NPs, but was significantly increased by Ag-NPs' presence for short and long-term incubations. Analyses of three key signaling proteins activated by IL-2 receptor (Stat5, JNK and ERK1/2) by western immunoblotting have shown no effects from either NPs on Stat5 and JNK phosphorylation. ERK1/2 was slightly activated following a short exposure to Ag-NPs, while C60-NPs had no effect. Our results show that C60-NPs have good biocompatibility and don't interfere with IL-2-dependent proliferation. A deeper investigation would be needed for the case of Ag-NPs, since the mechanism of their action is still unclear.
- T-cell-mediated cross-strain protective immunity elicited by prime-boost vaccination with a live attenuated influenza vaccine. [JOURNAL ARTICLE]
- Int J Infect Dis 2014 Aug 26.
Antigenic drift and shift of influenza viruses require frequent reformulation of influenza vaccines. In addition, seasonal influenza vaccines are often mismatched to the epidemic influenza strains. This stresses the need for a universal influenza vaccine.BALB/c mice were vaccinated with the trivalent live attenuated (LAIV; FluMist) or inactivated (TIV; FluZone) influenza vaccines and challenged with PR8 (H1N1), FM/47 (H1N1), or HK/68 (H3N2) influenza virus. Cytokines and antibody responses were tested by ELISA. Furthermore, different LAIV dosages were applied in BALB/c mice. LAIV vaccinated mice were also depleted of T-cells and challenged with PR8 virus.LAIV induced significant protection against challenge with the non-vaccine strain PR8 influenza virus. Furthermore, protective immunity against PR8 was dose-dependent. Of note, interleukin 2 and interferon gamma cytokine secretion in the lung alveolar fluid were significantly elevated in mice vaccinated with LAIV. Moreover, T-cell depletion of LAIV vaccinated mice compromised protection, indicating that T-cell-mediated immunity is required. In contrast, passive transfer of sera from mice vaccinated with LAIV into naïve mice failed to protect against PR8 challenge. Neutralization assays in vitro confirmed that LAIV did not induce cross-strain neutralizing antibodies against PR8 virus. Finally, we showed that three doses of LAIV also provided protection against challenge with two additional heterologous viruses, FM/47 and HK/68.These results support the potential use of the LAIV as a universal influenza vaccine under a prime-boost vaccination regimen.
- In vitro effects of oil's fatty acids on T cell function in gestational diabetic pregnant women and their newborns. [JOURNAL ARTICLE]
- J Diabetes 2014 Aug 28.
The aim of this investigation was to determine the in-vitro effects of linseed, olive and Nigel oils on T cell proliferation and function in gestational diabetes.Blood samples were collected from 40 control healthy and 32 gestational diabetic mothers and their newborns. Peripheral blood lymphocytes were isolated using a density gradient of Ficoll. T cell proliferation, interleukin-2 and -4 (IL-2, IL-4) secretion, fatty acid composition and intracellular oxidative status were investigated.Mitogen (Concanavalin A) stimulated lymphocyte proliferation, IL-2 secretion, intracellular reduced glutathione levels, SOD and catalase activities were lower while intracellular MDA and carbonyl proteins were higher in diabetic mothers and in their newborns as compared to their respective controls. Linseed oil induced a reduction in T-lymphocyte proliferation and IL-2 production, and alpha linolenic acid membrane enrichment in both diabetic and control groups. In the presence of Nigel oil, T-lymphocyte proliferation and IL-2 secretion, phospholipid linoleic and oleic acids were enhanced. Olive oil had no effect on lymphocyte proliferation in all groups. Linseed, olive and Nigel oils induced an increase in T cell levels of reduced glutathione levels and in activities of catalase and SOD with a concomitant decrease in MDA and carbonyl protein contents.Linseed, olive and Nigel oils had beneficial effects on T cell functions in gestational diabetes.
- Interleukin-2 receptor antagonist therapy leads to increased tacrolimus levels after kidney transplantation. [JOURNAL ARTICLE]
- Ther Drug Monit 2014 Aug 26.
Tacrolimus is a known substrate for cytochrome P450 (CYP) enzyme. CYP enzyme activity can be modulated via activation of IL-2 receptors (IL-2R) expressed on hepatocytes and intestinal cells. IL-2R antagonists (IL-2RA) may promote preferential binding of circulating IL-2 to IL-2Rs on these cells by blocking IL-2Rs on activated T-cells. This down-regulates CYP enzymes, leading to increased CNI levels. This analysis evaluates the significance of this drug-drug interaction in kidney transplant recipients.Data was utilized from a previous 5-year randomized, controlled study comparing outcomes associated with maintenance immunosuppression using 2 corticosteroid regimens: long-term therapy versus early withdrawal. Patients received either IL-2RAs or anti-thymocyte globulin (rATG) for induction. Serial tacrolimus trough levels and doses were compared between induction agents within each corticosteroid arm. Rejection rates, patient/graft survival and tacrolimus adverse effects were also evaluated.In the first week, IL-2RA-treated patients achieved significantly higher trough levels and required lower doses (mg/kg) to achieve target levels than rATG-treated patients. No significant differences in rejection rates, patient/graft survival or rate of adverse effects were observed through 1 year.
- Chronic Ethanol Exposure Selectively Inhibits the Influenza-Specific CD8 T Cell Response During Influenza A Virus Infection. [JOURNAL ARTICLE]
- Alcohol Clin Exp Res 2014 Aug 26.
It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza A virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce interferon γ (IFNγ). However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown.Utilizing the Meadows-Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV, and the activation and effector functions of IAV-specific CD8 T cells were determined in both the lung-draining lymph nodes (dLN) and lungs.Our results confirm the defect in IFNγ production; however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the dLN of IAV-infected, EtOH-consuming mice.These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.
- NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain. [JOURNAL ARTICLE]
- BMC Complement Altern Med 2014 Aug 26; 14(1):316.
Cumulating evidence has revealed the effectiveness of acupuncture therapy in relieving pain via immunoregulation. However, its underlying mechanism remains unknown. The present study was designed to determine the changes of immunogenic responses at different time-points of electroacupuncture (EA) interventions in neuropathic pain rats.The neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied at Zusanli (ST36) and Yanglingquan (GB34) for the EA groups. The thermal pain threshold was detected with an algesia-detector. The subgroups of plasma and splenic lymphocytes were determined via fluorescence-activated cell sorting. Specific inflammatory cytokines were assayed using an ELISA-based bead multiplex assay. The activities of splenic natural killer (NK) cells and cytotoxic T lymphocytes were detected by methyl thiazolyl tetrazolium colorimetric method. For confirming the involvement of NK cell in EA-analgesia, anti-asialo-ganglio-N-tetraosylceramide (anti-asialo-GM1) antibody was given to CCI rats before EA.Following CCI, the thermal pain threshold of the affected hind footpad was significantly decreased, and increased from the 3rd day to the 12th day after EA interventions, presenting a time-dependent tendency from the 5th day on. From day 3 to 5 of EA interventions, the percentages and activity of splenic NK cells, concentrations of splenic interleukin-2 (IL-2) and beta-endorphin (beta-EP) were significantly increased. Meanwhile, the concentrations of plasma IL-2, IL-1beta and gamma-interferon (IFN-gamma) were significantly decreased and returned to the normal level on day 12 following EA. Plasma transforming growth factor-beta (TGF-beta) levels were considerably upregulated on day 5 and 12 following EA. The CD4+/CD8+ T cell ratio was markedly downregulated compared with the control and CCI groups on day 5 and returned to the normal level on day 12 following EA. After depleting NK cells by anti-asialo-GM1 antibody, the increased thermal pain threshold following EA intervention was obviously reduced.Repeated EA interventions have a time-dependent cumulative analgesic effect in neuropathic pain rats, which is closely associated with its regulatory effects on NK cells, splenic IL-2, beta-EP, and plasma IL-2, IL-1beta, IFN-gamma and TGF-beta levels.
- Potassium currents inhibition by gambierol analogs prevents human T lymphocyte activation. [JOURNAL ARTICLE]
- Arch Toxicol 2014 Aug 26.
Gambierol is a marine polycyclic ether toxin, produced along with ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition in neurons. Gambierol and its truncated analogs share the main crucial elements for biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of gambierol on potassium currents in resting T lymphocyte and their effects on interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of gambierol in human T cells are: (1) inhibition of potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of gambierol have additional potential for the development of therapeutic tools in autoimmune diseases.
- Cytokine response in peripheral blood indicates different pathophysiological mechanisms behind anastomotic leakage after low anterior resection: a pilot study. [JOURNAL ARTICLE]
- Tech Coloproctol 2014 Aug 23.
Anastomotic leakage (AL) after rectosigmoid resection is a serious complication associated with high morbidity and mortality. This case-control pilot study investigated the changes in blood concentration of 10 different cytokines and 2 complement factors in relation to symptomatic AL after low anterior resection for rectosigmoid cancer.Fifty patients scheduled for resection of rectosigmoid cancer had blood samples taken the day before surgery and on post-operative days 1, 3 and 5. Four patients with symptomatic AL were identified. Twenty-two age- and disease-matched patients constituted the control group. The concentration of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-8, interleukin-10 and tumour necrosis factor-α) and 2 complement factors (mannan-binding lectin and membrane attack complex) were measured.The present study demonstrated that plasma concentration of interleukin-1β, interleukin-6, interleukin-8 and interleukin 10 within the first 5 post-operative days was increased in patients who developed early clinical AL, whereas there were no changes in patients with late-onset AL.The demonstrated differences in the cytokine response in early and late AL may support the theory of different pathological mechanisms of AL.
- Exogenous IL-2 Controls the Balance in Th1, Th17, and Treg Cell Distribution in Patients with Progressive Rheumatoid Arthritis Treated with TNF-Alpha Inhibitors. [JOURNAL ARTICLE]
- Inflammation 2014 Aug 22.
Interleukin-2 (IL-2) has been suggested to control Treg/Th17 balance. Recently, we reported a relationship of rheumatoid arthritis (RA) activity/progression with irreversible systemic Treg and Th1 defects including serum IL-2 shortage. Herein, we explore the role of in vitro stimulation with rIL-2 in the observed immune alterations reversal. Patients with stable or progressive RA were assigned to methotrexate (MTX) group or to TNF-alpha inhibitors (iTNF) group, respectively. Flow cytometric analyses were performed before and after 6 months of treatment. Circulating Th1, Th17, and Treg cells were determined before and after 72-h culture with anti-CD3 + rIL-2. Before therapy, 72-h stimulation restored recently observed phenotypic Th cell alterations, except for the enriched Th17 subset normalized as late as after therapy in all patients. Under 6-month therapy, anti-CD3 stimulation changed the Th cell distribution only in progressive RA; despite Th1 enrichment, it revealed Treg population defects, which were completely reversed by exogenous IL-2 added to the stimulating culture. Our paper shows that in aggressive RA patients exhibiting serum IL-2 shortage despite iTNF therapy, exogenous rIL-2 is capable of promoting Treg differentiation affected by chronic activation, thus supporting its use in the combined strategy of biologic treatment of the progressive form of RA.