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The Chinese Journal of Physiology 2020Whereas neuroimmune crosstalk between the sympathetic nervous system (SNS) and immune cells in the pathophysiology of hypertension is recognized, the exact effect of SNS...
Whereas neuroimmune crosstalk between the sympathetic nervous system (SNS) and immune cells in the pathophysiology of hypertension is recognized, the exact effect of SNS on T-lymphocyte in hypertension remains controversial. This study assessed the hypothesis that excitation of the SNS activates splenic T-lymphocytes through redox signaling, leading to the production of pro-inflammatory cytokines and the development of hypertension. Status of T-lymphocyte activation, reactive oxygen species (ROS) production and pro-inflammatory cytokines expression in the spleen were examined in a rodent model of hypertension programmed by maternal high fructose diet (HFD) exposure. Maternal HFD exposure enhanced SNS activity and activated both CD4 and CD8 T-lymphocytes in the spleen of young offspring, compared to age-matched offspring exposed to maternal normal diet (ND). Maternal HFD exposure also induced tissue oxidative stress and expression of pro-inflammatory cytokines in the spleen of HFD offspring. All those cellular and molecular events were ameliorated following splenic nerve denervation (SND) by thermoablation. In contrast, activation of splenic sympathetic nerve by nicotine treatment resulted in the enhancement of tissue ROS level and activation of CD4 and CD8 T-cells in the spleen of ND offspring; these molecular events were attenuated by treatment with a ROS scavenger, tempol. Finally, the increase in systolic blood pressure (SBP) programmed in adult offspring by maternal HFD exposure was diminished by SND, whereas activation of splenic sympathetic nerve increased basal SBP in young ND offspring. These findings suggest that excitation of the SNS may activate splenic T-lymphocytes, leading to hypertension programming in adult offspring induced by maternal HFD exposure. Moreover, tissue oxidative stress induced by the splenic sympathetic overactivation may serve as a mediator that couples the neuroimmune crosstalk to prime programmed hypertension in HFD offspring.
Topics: Blood Pressure; CD8-Positive T-Lymphocytes; Fructose; Humans; Hypertension; Spleen
PubMed: 33380611
DOI: 10.4103/CJP.CJP_85_20 -
Sensors (Basel, Switzerland) 2012It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to...
It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years) were taken before and immediately after ten sets of exercise consisting of 15 free and 30 10-kg loaded squat jumps in each set. The suppression of lymphocyte proliferation was analysed with high pressure liquid chromatography. It was noted from the result of gel chromatography columns that the post-exercise values of the suppression of lymphocyte proliferation, in comparison to corresponding pre-exercise values, were generally greater with significant differences observed in 7.5th-9th min post-exercise eluates (P < 0.05). Such findings suggest that intense eccentric type exercise may lead to generation of immunosuppressive factor(s) in young males.
Topics: Adult; Animals; Cell Proliferation; Exercise; Humans; Immunosuppressive Agents; Lymphocytes; Male; Mice; Stress, Physiological
PubMed: 22778602
DOI: 10.3390/s120505586 -
Arthritis Research & Therapy 2010B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor (TNF) family that regulate B-cell maturation,...
B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin.
INTRODUCTION
B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor (TNF) family that regulate B-cell maturation, survival, and function. They are overexpressed in a variety of autoimmune diseases and reportedly exist in vivo not only as homotrimers, but also as BLyS/APRIL heterotrimers.
METHODS
A proprietary N-terminal trimerization domain was used to produce recombinant BLyS/APRIL heterotrimers. Heterotrimer biologic activity was compared with that of BLyS and APRIL in a 4-hour signaling assay by using transmembrane activator and CAML interactor (TACI)-transfected Jurkat cells and in a 4-day primary human B-cell proliferation assay. A bead-based immunoassay was developed to quantify native heterotrimers in human sera from healthy donors (n = 89) and patients with systemic lupus erythematosus (SLE; n = 89) or rheumatoid arthritis (RA; n = 30). Heterotrimer levels were compared with BLyS and APRIL homotrimer levels in a subset of these samples.
RESULTS
The recombinant heterotrimers consisted mostly of one BLyS and two APRIL molecules. Heterotrimer signaling did not show any significant difference compared with APRIL in the TACI-Jurkat assay. Heterotrimers were less-potent inducers of B-cell proliferation than were homotrimeric BLyS or APRIL (EC(50), nMol/L: BLyS, 0.02; APRIL, 0.17; heterotrimers, 4.06). The soluble receptor fusion proteins atacicept and B-cell maturation antigen (BCMA)-immunoglobulin (Ig) neutralized the activity of BLyS, APRIL, and heterotrimers in both cellular assays, whereas B-cell activating factor belonging to the TNF family receptor (BAFF-R)-Ig neutralized only the activity of BLyS. In human sera, significantly more patients with SLE had detectable BLyS (67% versus 18%; P < 0.0001), APRIL (38% versus 3%; P < 0.0002), and heterotrimer (27% versus 8%; P = 0.0013) levels compared with healthy donors. Significantly more patients with RA had detectable APRIL, but not BLyS or heterotrimer, levels compared with healthy donors (83% versus 3%; P < 0.0001). Heterotrimer levels weakly correlated with BLyS, but not APRIL, levels.
CONCLUSIONS
Recombinant BLyS/APRIL heterotrimers have biologic activity and are inhibited by atacicept and BCMA-Ig, but not by BAFF-R-Ig. A novel immunoassay demonstrated that native BLyS/APRIL heterotrimers, as well as BLyS and APRIL homotrimers, are elevated in patients with autoimmune diseases.
Topics: Autoimmune Diseases; B-Cell Activating Factor; B-Cell Maturation Antigen; B-Lymphocytes; Cell Proliferation; Humans; Interleukin-4; Jurkat Cells; Lymphocyte Activation; Protein Multimerization; Recombinant Fusion Proteins; Recombinant Proteins; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 20302641
DOI: 10.1186/ar2959 -
Cellular Immunology Nov 1992Oxidants, heavy metals, and heat shock, collectively known as stress stimuli, induce the synthesis of a variety of proteins, termed stress proteins, and enhance glucose...
Oxidants, heavy metals, and heat shock, collectively known as stress stimuli, induce the synthesis of a variety of proteins, termed stress proteins, and enhance glucose uptake. In this study, we have demonstrated that stress stimuli enhance protein tyrosine phosphorylation (PTyr-P), modulate protein tyrosine phosphatase (PTPase) activity, activate the src family protein tyrosine kinase (PTK), p56lck, and enhance glucose uptake in human peripheral blood mononuclear cells. The heavy metal Hg2+ and heat shock stimulated PTPase activity at an optimal dose, whereas the oxidant phenylarsine oxide (PAO) was only marginally stimulatory. Treatment of lymphocytes with stress stimuli at a dose which activated PTPase did not produce discernable PTyr-P using Western blotting techniques. PTyr-P was only seen at doses of stress stimuli which were associated with an inhibition of PTPase activity. We could demonstrate a correlation between the dose of stress stimuli effective in increasing PTPase activity and p56lck activation using heat shock and Hg2+ as stress stimuli. On the other hand, much lower concentrations of PAO were effective in activating PTPase than those effective in eliciting p56lck activation. We could not demonstrate a correlation between an effective dose inducing PTyr-P and glucose uptake. Our data do not permit us to draw a simple correlation between enhancement of PTPase activity, activation of p56lck, induction of PTyr-P, and induction of the biological response. It is possible that both stimulation and inhibition of PTPase could regulate PTyr-P by either activating the src family PTKs or preventing dephosphorylation of target proteins which are involved in the biological response. Our data may also provide the biochemical basis for the previously reported mitogenic effects of Hg2+ on lymphocytes.
Topics: Cells, Cultured; Glucose; Humans; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Lymphocytes; Phosphorylation; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins; Stress, Physiological; Tyrosine
PubMed: 1423640
DOI: 10.1016/0008-8749(92)90319-k -
International Journal of Oncology Aug 2014Many observational epidemiologic studies suggest an association between exercise and colon cancer risk. The mechanisms contributing to a preventative effect of exercise...
Many observational epidemiologic studies suggest an association between exercise and colon cancer risk. The mechanisms contributing to a preventative effect of exercise on colon cancer are complex and multifaceted. Altered immune system function is one possible mechanism that has been largely unexplored. Therefore, the purpose of this study was to examine the effects of exercise on markers associated with macrophages and select T cell populations in a mouse model of intestinal tumorigenesis and to relate this to polyp characteristics. Male Apc(Min/+) mice were randomly assigned to either sedentary (Sed) or exercise (Ex) treatment (n=6-9/group). The exercise treatment consisted of treadmill running for 1 h/day and 6 days a week at 15 m/min from 4 until 16 weeks of age. Intestinal polyps were counted and categorized by size. Mucosal tissue was analyzed for mRNA expression of overall macrophages (F4/80), for genes associated with M1 (IL-12, IL-23 and Nos2) and M2 (CD206, IL-10, IL-4, CCL17, CCL22 and Arg-1) macrophages and the macrophage chemoattractants MCP-1, fetuin A and CXCL14. Markers for cytotoxic T cells (CTLs) and regulatory T cells were also examined by measuring mRNA expression of CD8 and Foxp3, respectively. While there was no significant difference in overall polyp number between the groups (Sed, 23.3±4.3; and Ex, 16.5±4.3), Ex did have a reduction in the number of large polyps (Sed, 6.1±1.1; and Ex, 3.0±0.6) (P<0.05). This was consistent with a decrease in spleen weight (P<0.05). Similarly, Ex reduced mRNA expression of overall macrophages (F4/80) as well as markers associated with both M1 (IL-12) and M2 (CD206, CCL22 and Arg-1) subtypes (P<0.05) but there was no significant decrease in macrophage chemoattractants. CD8 expression was increased while Foxp3 expression was decreased with Ex (P<0.05). Overall the data provide important new information on immune regulation as a possible mechanism for the documented benefits of exercise training on reducing colon cancer progression.
Topics: Animals; Cell Transformation, Neoplastic; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Intestinal Polyps; Macrophages; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Motor Activity; Precancerous Conditions; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 24859893
DOI: 10.3892/ijo.2014.2457 -
Journal of Applied Physiology... Jun 2002This study utilized recently developed microbead technology to remove natural killer (NK) cells from peripheral blood mononuclear cell (PBMC) preparations to determine... (Comparative Study)
Comparative Study
This study utilized recently developed microbead technology to remove natural killer (NK) cells from peripheral blood mononuclear cell (PBMC) preparations to determine the effect of acute exercise on T-lymphocyte function, independent of changes in lymphocyte subpopulations. Twelve well-trained male runners completed a 60-min exercise trial at 95% ventilatory threshold and a no-exercise control trial. Six blood samples were taken at each session: before exercise, midexercise, immediately after exercise, and 30, 60, and 90 min after exercise. Isolated PBMC and NK cell-depleted PBMC were stimulated with the mitogen phytohemagglutinin. Cellular proliferation was assessed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye uptake. In the PBMC cultures, there was a significantly lower mitogen response to phytohemagglutinin in exercise compared with the control condition immediately postexercise. There were no significant differences between the control and exercise conditions in NK cell-depleted PBMC cultures or in the responses adjusted for the percentage of CD3 cells. The present findings do not support the view that T-lymphocyte function is reduced after exercise.
Topics: Adult; CD3 Complex; Cell Division; Cells, Cultured; Exercise; Humans; Killer Cells, Natural; Leukapheresis; Leukocyte Count; Male; Monocytes; Phytohemagglutinins; Reference Values; Running; T-Lymphocytes; Time Factors
PubMed: 12015352
DOI: 10.1152/japplphysiol.00926.2001 -
Journal of Thrombosis and Haemostasis :... Mar 2016ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were...
UNLABELLED
ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were investigated in an in vitro coculture system. Different regulatory roles of BAFF were investigated via different receptors in immune thrombocytopenia. The upregulated BAFF receptors on autoreactive lymphocytes lead to their hypersensitivity to BAFF.
BACKGROUND
The pathogenesis of immune thrombocytopenia (ITP) remains enigmatic. B-cell-activating factor (BAFF) and its receptors (BAFF receptor [BAFF-R], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and B-cell maturation antigen) play central roles in the integrated homeostatic regulation of lymphocytes.
OBJECTIVES
To investigate the pathologic roles of BAFF receptors in regulating the bioactivities of lymphocytes in ITP.
METHODS
An in vitro culture system was established by stimulating CD14(-) peripheral lymphocytes with platelet-preloaded dendritic cells in the presence of recombinant human BAFF (rhBAFF; 20 ng mL(-1)). The functions of BAFF receptors were specifically blocked with blocking antibodies.
RESULTS
BAFF-R, besides prolonging the survival of B cells in both patients and healthy controls, prominently promoted the survival of CD8(+) T cells and the proliferation of B cells in patients with ITP. TACI, as a positive regulator, not only promoted the proliferation of CD4(+) and CD8(+) T cells, but also significantly enhanced the secretion of interleukin-4 in patients with ITP, but not in controls. Besides revealing the pathologic roles of BAFF receptors, these results also indicate that lymphocytes of patients with ITP have enhanced antiapoptotic or proliferative capacity as compared with those from healthy controls when exposed under similar stimulation of rhBAFF. Further study demonstrated that activated autoreactive B cells and CD4(+) T cells from patients with ITP showed significantly higher expression of BAFF-R or TACI than those from healthy controls.
CONCLUSIONS
Both BAFF-R and TACI are pathogenic participants in ITP. Their dysregulated expression in patients with ITP may lead to hyperreactivity of activated autoreactive lymphocytes in response to rhBAFF, and thus is highly significant in the pathogenesis of ITP.
Topics: Adolescent; Adult; Aged; Apoptosis; B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Lymphocytes; Blood Platelets; Case-Control Studies; Cell Proliferation; Cells, Cultured; Chronic Disease; Coculture Techniques; Cytokines; Dendritic Cells; Female; Humans; Lymphocyte Activation; Male; Middle Aged; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Purpura, Thrombocytopenic, Idiopathic; Signal Transduction; T-Lymphocytes; Transmembrane Activator and CAML Interactor Protein; Young Adult
PubMed: 26749059
DOI: 10.1111/jth.13246 -
Frontiers in Immunology 2023The aim of this study is to analyze whether immune responses after strenuous exercise are influenced by chronological age and fitness level in physically active healthy...
AIM
The aim of this study is to analyze whether immune responses after strenuous exercise are influenced by chronological age and fitness level in physically active healthy men.
METHODS
Cross-sectional study with a sample of 32 physically active men. Participants were divided into two groups based on chronological age (younger: age 21.8 ± 1.8 vs. older: age 34.6 ± 8.3) and subsequently regrouped and divided based on fitness level (More conditioned: excellent and superior VO2max vs. Less conditioned: VO2max: weak, regular and good). Fitness was classified according to VO2max levels obtained by a treadmill test using a gas analyzer. Before and immediately after the ergospirometry test, blood samples were collected for evaluation of immunological markers: leukocytes, neutrophils, lymphocytes and subpopulations.
RESULTS
Chronological age had a moderate effect on CD3+CD4+ lymphocyte count (effect size: 0.204) and CD4/CD8 ratio (effect size: 0.278), favoring older subjects. The level of physical fitness had no significant effect on the analyzed immunological markers.
CONCLUSIONS
Immune responses observed immediately after strenuous exercise may be more dependent on chronological age than on fitness level in healthy, physically active men.
Topics: Male; Humans; Young Adult; Adult; Cross-Sectional Studies; Exercise; Killer Cells, Natural; Physical Fitness; Immunity
PubMed: 37860003
DOI: 10.3389/fimmu.2023.1252506 -
Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.Purinergic Signalling Mar 2016Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine...
Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI.
Topics: Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Animals; Animals, Newborn; Brain; Brain Ischemia; CD4-Positive T-Lymphocytes; Cerebral Infarction; Female; Hypoxia, Brain; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Myeloid Cells; Postural Balance; Pregnancy; Receptor, Adenosine A1
PubMed: 26608888
DOI: 10.1007/s11302-015-9482-3 -
Scientific Reports Oct 2016This study elucidates how interval and continuous exercise regimens affect the mitochondrial functionality of lymphocytes under hypoxic stress. Sixty healthy sedentary... (Randomized Controlled Trial)
Randomized Controlled Trial
This study elucidates how interval and continuous exercise regimens affect the mitochondrial functionality of lymphocytes under hypoxic stress. Sixty healthy sedentary males were randomly assigned to engage in either high-intensity interval training (HIIT, 3 min intervals at 80% and 40% VO, n = 20) or moderate-intensity continuous training (MICT, sustained 60% VO, n = 20) for 30 min/day, 5 days/week for 6 weeks or were assigned to a control group that did not receive exercise intervention (n = 20). Lymphocyte phenotypes/mitochondrial functionality under hypoxic exercise (HE, 100 W under 12% O) were determined before and after the various interventions. Before the intervention, HE (i) increased the mobilization of senescent (CD57/CD28) lymphocytes into the blood, (ii) decreased the ATP-linked O consumption rate (OCR), the reserve capacity of OCR, and the citrate synthase activity in the mitochondria, and (iii) lowered the mitochondrial membrane potential (MP) and elevated the matrix oxidant burden (MOB) of lymphocytes. However, both HIIT and MICT significantly (i) decreased blood senescent lymphocyte counts, (ii) enhanced the mitochondrial OCR with increased citrate synthase and succinate dehydrogenase activities, (iii) increased mitochondrial MP and decreased MOB and (iv) increased the ratio of mitofusin to DRP-1 in lymphocytes after HE. Thus, we concluded that either HIIT or MICT effectively improves lymphocyte mitochondrial functionality by enhancing oxidative phosphorylation and suppressing oxidative damage under hypoxic conditions.
Topics: Citric Acid Cycle; Epinephrine; Exercise; Glycolysis; High-Intensity Interval Training; Humans; Hypoxia; Lymphocytes; Male; Membrane Potential, Mitochondrial; Mitochondria; Norepinephrine; Organelle Biogenesis; Oxidative Phosphorylation; Oxygen Consumption; Phenotype; Physical Conditioning, Human; Sedentary Behavior; Young Adult
PubMed: 27731374
DOI: 10.1038/srep35170