Dose-Dependent Association of Inflammatory Cytokines with Carotid Atherosclerosis in Transient Ischaemic Attack: Implications for Clinical Trials

2021 ◽  
pp. 1-10
Author(s):  
Sarah Coveney ◽  
John J. McCabe ◽  
Sean Murphy ◽  
Orina Belton ◽  
Cleona Gray ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Transient Ischaemic Attack ◽  
Carotid Atherosclerosis ◽  
High Sensitivity ◽  
Symptomatic Carotid ◽  
Tnf Α ◽  
Ischaemic Attack ◽  
Plaque Inflammation ◽  
Ifn Γ ◽  
Dose Dependent

<b><i>Introduction:</i></b> The 5-year recurrence risk after ischaemic stroke and transient ischaemic attack (TIA) is 25–30%. Although inflammation may be a target for prevention trials, the contribution of plaque inflammation to acute cerebrovascular events remains unclear. We investigated the association of acute inflammatory cytokines and high-sensitivity C-reactive protein (CRP) with recently symptomatic carotid atherosclerosis in a prospective cohort study. <b><i>Methods:</i></b> Blood and Imaging markers of TIA BIO-TIA) is a multicentre prospective study of imaging and inflammatory markers in patients with TIA. Exclusion criteria were infection and other co-morbid illnesses associated with inflammation. CRP and serum cytokines (interleukin [IL]-6, IL-1β, IL-8, IL-10, IL-12, interferon-γ [IFN-γ] and tumour necrosis factor-α [TNF-α]) were measured. All patients had carotid imaging. <b><i>Results:</i></b> Two hundred and thirty-eight TIA cases and 64 controls (TIA mimics) were included. Forty-nine (20.6%) cases had symptomatic internal carotid artery stenosis. Pro-inflammatory cytokine levels increased in a dose-dependent manner across controls, TIA without carotid stenosis (CS), and TIA with CS (IL-1β, <i>p</i><sub>trend</sub> = 0.03; IL-6, <i>p</i><sub>trend</sub> &#x3c; 0.0001; IL-8, <i>p</i><sub>trend</sub> = 0.01; interferon (IFN)-γ, <i>p</i><sub>trend</sub> = 0.005; TNF-α, <i>p</i><sub>trend</sub> = 0.003). Results were unchanged when DWI-positive cases were excluded. On multivariable linear regression, only age (<i>p</i> = 0.01) and CS (<i>p</i> = 0.04) independently predicted log-IL-6. On multivariable Cox regression, CRP was the only independent predictor of 90-day stroke recurrence (adjusted hazard ratio per 1-unit increase 1.03 [95% CI: 1.01–1.05], <i>p</i> = 0.003). <b><i>Conclusion:</i></b> Symptomatic carotid atherosclerosis was associated with elevated cytokines in TIA patients after controlling for other sources of inflammation. High-sensitivity CRP was associated with recurrent ischaemic stroke at 90 days. These findings implicate acute plaque inflammation in the pathogenesis of cerebral thromboembolism and support a rationale for randomized trials of anti-inflammatory therapy for stroke patients, who were excluded from coronary trials.

scholarly journals Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study

Endocrine ◽  
2021 ◽  
Author(s):  
Francesca Coperchini ◽  
Gianluca Ricci ◽  
Laura Croce ◽  
Marco Denegri ◽  
Rubina Ruggiero ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Combination Treatment ◽  
Primary Cultures ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Mrna Levels ◽  
Thyroid Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Introduction Angiotensin-converting-enzyme-2 (ACE-2) was demonstrated to be the receptor for cellular entry of SARS-CoV-2. ACE-2 mRNA was identified in several human tissues and recently also in thyroid cells in vitro. Purpose Aim of the present study was to investigate the effect of pro-inflammatory cytokines on the ACE-2 mRNA levels in human thyroid cells in primary cultures. Methods Primary thyroid cell cultures were treated with IFN-γ and TNF-α alone or in combination for 24 h. ACE-2 mRNA levels were measured by RT-PCR. As a control, the levels of IFN-γ inducible chemokine (CXCL10) were measured in the respective cell culture supernatants. Results The mean levels of ACE-2 mRNA increased after treatment with IFN-γ and TNF-α in all the thyroid cell preparations, while the combination treatment did not consistently synergically increase ACE-2-mRNA. At difference, CXCL10 was consistently increased by IFN-γ and synergically further increased by the combination treatment with IFN-γ + TNF-α, with respect to IFN-γ alone. Conclusions The results of the present study show that IFN-γ and, to a lesser extent TNF-α consistently increase ACE-2 mRNA levels in NHT primary cultures. More interestingly, the combined stimulation (proven to be effective according to the synergic effect registered for CXCL10) produces different responses in terms of ACE-2 mRNA modulation. These results would suggest that elevated levels of pro-inflammatory cytokines could facilitate the entering of the virus in cells by further increasing ACE-2 expression and/or account for the different degree of severity of SARS-COV-2 infection. This hypothesis deserves to be confirmed by further specific studies.

scholarly journals Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shengchao Zhang ◽  
Jiankai Fang ◽  
Zhanhong Liu ◽  
Pengbo Hou ◽  
Lijuan Cao ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
Human Muscle ◽  
Enzyme Linked Immunosorbent Assay ◽  
Muscle Stem Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory

Abstract Background Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored. Methods The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression. Results hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR). Conclusion Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.

scholarly journals Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

2018 ◽  
Vol 46 (3) ◽  
pp. 1241-1251 ◽  
Author(s):  
Tinghong Ye ◽  
Tingting Wang ◽  
Xiaoxue Yang ◽  
Xiaoli Fan ◽  
Maoyao Wen ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Inflammatory Cytokines ◽  
Concanavalin A ◽  
Current Treatment ◽  
Human Condition ◽  
Type I ◽  
Therapeutic Approaches ◽  
Tnf Α ◽  
Ifn Γ ◽  
New Treatments

Background/Aims: Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. Methods: AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. Results: Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4+ and CD8+ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. Conclusion: This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

scholarly journals Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells

2019 ◽  
Vol 331 ◽  
pp. 36-45 ◽  
Author(s):  
Sanna Hagman ◽  
Aliisa Mäkinen ◽  
Laura Ylä-Outinen ◽  
Heini Huhtala ◽  
Irina Elovaara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Inflammatory Cytokines ◽  
Pluripotent Stem Cell ◽  
Neural Cells ◽  
Human Pluripotent Stem Cell ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals 1,25(OH)2D3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ

2019 ◽  
Vol 8 (12) ◽  
pp. 2211 ◽  
Author(s):  
Christian Behm ◽  
Alice Blufstein ◽  
Johannes Gahn ◽  
Barbara Kubin ◽  
Michael Nemec ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
T Lymphocyte ◽  
T Lymphocyte Proliferation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Necrosis Factor

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines.

scholarly journals Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes

2006 ◽  
Vol 100 (4) ◽  
pp. 1124-1133 ◽  
Author(s):  
Frank Zaldivar ◽  
Jessica Wang-Rodriguez ◽  
Dan Nemet ◽  
Christina Schwindt ◽  
Pietro Galassetti ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Inflammatory Cytokines ◽  
Fluorescence Intensity ◽  
Healthy Humans ◽  
Intracellular Cytokines ◽  
Tnf Α ◽  
Igf I ◽  
Ifn Γ ◽  
Anti Inflammatory

Leukocytosis following exercise is a well-described phenomenon of stress/inflammatory activation in healthy humans. We hypothesized that, despite this increase in circulating inflammatory cells, exercise would paradoxically induce expression of both pro- and anti-inflammatory cytokines and growth factors within these cells. To test this hypothesis, 11 healthy adult men, 18–30 yr old, performed a 30-min bout of heavy cycling exercise; blood sampling was at baseline, end-exercise, and 60 min into recovery. The percentage of leukocytes positive for intracellular cytokines and growth factors and mean fluorescence intensity was obtained by flow cytometry. Proinflammatory cytokines (IL-1α, IL-2, IFN-γ, and TNF-α), a pleiotropic cytokine (IL-6), and anti-inflammatory cytokines and growth factors [IL-4, IL-10, growth hormone (GH), and IGF-I] were examined. Median fluorescence intensity was not affected by exercise; however, we found a number of significant changes ( P < 0.05 by mixed linear model and modified t-test) in the numbers of circulating cells positive for particular mediators. The pattern of expression reflected both pro- and anti-inflammatory functions. In T-helper lymphocytes, TNF-α, but also IL-6, and IL-4 were significantly increased. In monocytes, both IFN-γ and IL-4 increased. B-lymphocytes positive for GH and IGF-I increased significantly. GH-positive granulocytes also significantly increased. Collectively, these observations indicate that exercise primes an array of pro- and anti-inflammatory and growth factor expression within circulating leukocytes, perhaps preparing the organism to effectively respond to a variety of stressors imposed by exercise.

The content of cytokines IL-6, IL-8, TNF-α, IL-4 and the level of expression in macrophages CD86 and CD163 in peritoneal fluid has a reverse correlation with the degree of severity of external genital endometriosis

2019 ◽  
Vol 65 (5) ◽  
pp. 432-436
Author(s):  
A.M. Krasnyi ◽  
A.A. Sadekova ◽  
T.G. Sefihanov ◽  
V.V. Vtorushina ◽  
E.G. Krechetova ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Peritoneal Fluid ◽  
Inflammatory Marker ◽  
Inflammatory Activity ◽  
Control Group ◽  
Reverse Correlation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Degree Of Severity

Concentrations of eight different cytokines and the level of expression of CD86 and CD163 macrophages were studied in peritoneal fluid in women with endometriosis. It was found that the concentration of both inflammatory (IL-6, IL-8, TNF-α) and anti-inflammatory cytokines (IL-4) as well as the level of macrophage expression of the proinflammatory marker CD86 and anti-inflammatory marker CD163 increased in women with mild external genital endometriosis (1-2 stage), and did not differ from the control group in women with severe endometriosis (3-4 stage). The content of IL-2, IL-10, CM-CSF and IFN-γ in the peritoneal fluid of women with endometriosis did not differ significantly from the control group. The results of the study indicate that the development of external genital endometriosis may be based on insufficient both inflammatory and anti-inflammatory activity of macrophages in the peritoneal fluid.

scholarly journals Plasma cytokine response in mice with bacterial infection

2000 ◽  
Vol 9 (5) ◽  
pp. 229-234 ◽  
Author(s):  
Maja Abram ◽  
Darinka Vučković ◽  
Branka Wraber ◽  
Miljenko Doric
Keyword(s):  
Bacterial Infection ◽  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Clinical Status ◽  
Blood Levels ◽  
Large Individual ◽  
Bacterial Number ◽  
Tnf Α ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Background:Exposure to microorganisms elicts the production of cytokines. These soluble factors enhance several innate immune functions and regulate the ensuing specific immune response aimed at limiting the spread of infection.Aim:This study was undertaken to quantify the plasma levels of pro-inflammatory cytokines during the course of primaryListeria monocytogenesandCampylobacter jejuniinfection. Using anin vivoinfection the relationship between endogenous cytokines and the bacterial number in the liver of infected animals was examined.Methods:C57BL/6 mice were infected by the intraperitoneal route. At different time points we determined the number of colony-forming units of bacteria in the liver of infected animals and paralled these with the plasma levels of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) measured by enzyme immunoassays.Results:L. monocytogenes infection lasted 10–11 days. IFN-γ production occurred in the early phase but was more pronounced after day 4, following the appearance of specific immunity. The duration of experimental campylobacteriosis was 15 days. Early IFN-γ production was not significant but a progressive rise of this cytokine in plasma was seen during the second week post infection. Mice produced measurable amounts of plasma TNF-α immediately after being given viableL. monocytogenes, peaking on day 2–3 when the greatest number of bacteria was present in the examined organs. DuringC. jejuniinfection plasma TNF-α was produced in a similar manner, but the highest concentrations were found a few days later than in listeriosis, in correlation with the different course of campylobacteriosis. The quantity of IL-6 increased and decreased in concordance with clearance ofL. monocytogenesand the clinical status of the animals.C. jejunidid not promote the induction of this cytokine. This is to some extent an unusual finding. With respect to the role of IL-6 in Th2 responses and antibody production, the appearance of this cytokine in campylobacteriosis was more expected.Discussion:During systemic bacterial infection, a network of pro-inflammatory cytokines is activated and blood levels of these cytokines are elevated, albeit inconsistently, with large individual variations and depending on microbial characteristics and structure.

scholarly journals Effects of Toosendanin on Pregnancy and Uterine Immunity Alterations in Mice

2010 ◽  
Vol 38 (02) ◽  
pp. 319-328 ◽  
Author(s):  
Jian-Lou Zhang ◽  
Wang-Yu Shi ◽  
Wei Zhong ◽  
Ai-Tuan Ma ◽  
Xiao-Dan Wang ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Herbal Medicine ◽  
Chinese Herbal Medicine ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chinese Herbal ◽  
Cd8 T Lymphocytes ◽  
Tnf Α ◽  
Ifn Γ ◽  
Th1 Cytokines ◽  
Dose Dependent

This study was conducted to explore the abortifacient effect and the mechanisms of the Chinese herbal medicine component toosendanin, and to elucidate the significance of the Th1 cytokines IFN-γ and TNF-α, CD4+ and CD8+ T lymphocytes in the occurrence of abortion. Graded doses of toosendanin were given by intraperitoneal injection (i.p.) to mice at day 5, 6, 7 of gestation. The levels of Th1 cytokines (IFN-γ, TNF-α) in serum and uterine tissues from mice sacrificed at day 8 were analyzed by enzyme linked immunosorbent assay (ELISA). Presence of T lymphocytes in endometrium was detected by immunohistochemistry. The results revealed that injection of toosendanin could produce a dose-dependent toxicity. The IFN-γ, TNF-α content in serum and uterine tissues were increased significantly. The CD4+ and CD8+ T lymphocytes were also increased in the endometrium of toosendanin treated groups. In conclusion, toosendanin is pregnancy-toxic to animals and it is relevant to the increased contents of IFN-γ, TNF-α and CD4+, CD8+ T lymphocytes.

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