Anti-Inflammatory Effect of Hydroxyurea Therapy in Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3806-3806 ◽  
Author(s):  
Carolina Lanaro ◽  
Carla F. Franco-Penteado ◽  
Nicola Conran ◽  
Sara T.O. Saad ◽  
Fernando F. Costa
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Healthy Controls ◽  
Cell Disease ◽  
Inflammatory Biomarker ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Hydroxyurea Therapy

Abstract There is growing evidence that inflammatory stresses within the microvasculature may play a significant role in the vaso-occlusion that is characteristic of sickle cell disease. Inflammation, leukocyte adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to the pathogenesis of SCD. Whilst alterations in a number of inflammatory, anti-inflammatory cytokines and inflammatory biomarkers have been previously related, reports have been conflicting and a conclusive role for cytokines in SCD remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not well understood. This study was undertaken to determine plasma levels of IL-8, IL-10, TNF-a and PGE2 in healthy controls, SCD patients in steady-state and in SCD patients on HU therapy (SCDHU; 20–30 mg/kg/day; 3-month minimum treatment duration) using specific ELISA assays (R&D Research). TNF-a levels were significantly higher in SCD individuals when compared to controls (2.95 ± 0.44 pg/ml, n=17; vs 1.43 ± 0.20 pg/ml, n=8, p=0.006). HU therapy, however, was observed to significantly reverse augmented TNF-a levels (SCDHU; 1.61 ± 0.18 pg/ml, n=15, p=0.007). Plasma IL-8 levels were significantly elevated in SCD individuals (16.58 ± 2.52 pg/ml, n=29, p<0.001) compared to healthy controls (5.67 ± 0.62 pg/ml, n=16); however HU therapy did not significantly alter augmented IL-8 in SCD (14.59 ± 1.57 pg/ml, n=22). Interestingly, detectable levels of the anti-inflammatory cytokine, IL-10 (>3.8 pg/ml), were found in 3 (15%) of 20 SCD patients, and 1 (11%) of 9 controls, whilst 7 (50%) of 14 HU-treated patients demonstrated detectable IL-10 levels. Levels of plasma PGE2, an inflammatory biomarker, were significantly increased in SCD patients compared to control individuals (128.35 ± 12.25 pg/ml, n=26; vs 88.45 ± 5.95 pg/ml, n=14, p=0.01) and similar levels were detected in patients treated with HU (143.6 ± 16.75 pg/ml, n=17, p=0.004, compared to control). Data demonstrate that the inflammatory cytokines, TNFa and IL-8, and the inflammatory biomarker, PGE2, are augmented in a population of SCD patients studied during steady-state, contributing to clarify conflicting data. Furthermore, HU therapy reversed augmented TNFa levels, and appears to have an augmenting effect on the anti-inflammatory cytokine, IL-10, suggesting an anti-inflammatory action of HU therapy that may be important for the prevention of vaso-occlusion.

scholarly journals Microglial phenotypes in the human epileptic temporal lobe

Brain ◽  
2018 ◽  
Vol 141 (12) ◽  
pp. 3343-3360 ◽  
Author(s):  
Mélanie Morin-Brureau ◽  
Giampaolo Milior ◽  
Juliette Royer ◽  
Farah Chali ◽  
Caroline Le Duigou ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Temporal Lobe ◽  
Inflammatory Cytokine ◽  
Anatomical Studies ◽  
Microglial Phenotype ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

Using transcriptomics, anatomical studies, imaging and ELISA, Morin-Brureau et al. examine microglia in patients with temporal lobe epilepsies. In highly sclerotic regions such as CA1, the anti-inflammatory cytokine IL-10 regulates microglial phenotype. Seizures induce a transient microglial phenotype associated with secretion of inflammatory cytokines including human CXCL8.

scholarly journals P0527AROLE OF PROMOTING INFLAMMATION OF KLF6 IN ACUTE KIDNEY INURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dan Li ◽  
Chenyu Li ◽  
Yan Xu
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tnf Α ◽  
Public Dataset ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims Acute kidney injury (AKI), commonly appeared in cardiac arrest, surgery and kidney transplantation which involved in ischemia-reperfusion (IR) injury of kidney. However, the mechanisms underlying inflammatory response in IR AKI is still unclear. Method Public dataset showed kruppel-like factor 6 (KLF6) was significantly highly expressed (P&lt;0.05) in AKI, implies KLF6 might be associated with AKI. To evaluate the mechanism of KLF6 on IR AKI, 30 rats were randomly divided into sham and IR group, and were sacrificed at 0 h, 3 h, 6 h, 12 h or 24 h after IR. Results The results showed KLF6 expression was peaking at 6 h after IR, and the expression of pro-inflammatory cytokines MCP-1 and TNF-α were increased both in serum and kidney tissues after IR, while anti-inflammatory cytokine IL-10 was decreased after IR. Furthermore, in vitro results showed KLF6 knock-down reduced the pro-inflammatory cytokines expression and increased the anti-inflammatory cytokines expression. Conclusion These results suggest that (1) KLF6 might be a novel biomarker for early diagnosis of AKI and (2) targeting KLF6 expression may offer novel strategies to protect kidneys from IR AKI Figure KLF6, AKI, Control Inflammation

Production and Expression of Inflammatory Mediators in Leukocytes of Sickle Cell Anaemia Patients and Effects of Hydroxyurea Therapy on This Production

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2490-2490
Author(s):  
Carolina Lanaro ◽  
Carla Fernanda Franco-Penteado ◽  
Dulcinéia M Albuquerque ◽  
Sara T.O. Saad ◽  
Nicola Conran ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Inflammatory Mediators ◽  
Healthy Controls ◽  
Gene Expressions ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Hydroxyurea Therapy

Abstract Leukocytosis is frequently observed in sickle cell disease (SCD) in the absence of bacterial infection. An elevated baseline leukocyte count is associated with an increased risk of early death and leukocytes play a significant role in the initiation of vaso-occlusive events. Inflammation, cell adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to sickle cell anemia (SCA) vaso-occlusion. Furthermore, blood levels of inflammatory and anti-inflammatory cytokines are reported to be elevated (TNF-α, IL-6, IL-10, GM-CSF), both in steady state and during crisis, but reports have been conflicting and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls (n=30), steady-state SCA patients (n=45) and SCA patients on HU therapy (n=24). qRT-PCR analysis was use to examine gene expression and ELISA protein production. TNF-α, IL-8 and PGE2 plasma levels were significantly higher in the plasma of steady-state SCA individuals, when compared to control individuals (2.95 ± 0.4 pg/ml; 16.5 ± 2.5 pg/ml; 5.7 ± 0.6 pg/ml; 128.3 ± 12.2 pg/ml vs 1.43 ± 0.2 pg/ml, 88.5 ± 5.9 pg/ml, P=0.006; P&lt;0.0001; P=0.012, respectively). HU therapy significantly reversed augmented TNF-α (1.6 ± 0.2 pg/ml, P=0.006) and, interestingly, increased plasma anti-inflammatory IL-10 (P&lt;0.05). IL-10, IFN-γ, COX-2 and iNOS gene expressions were unaltered in SCA mononuclear cells (MC), however gene expressions of TNF-α, IL-8 and the protective enzyme, heme oxygenase-1 (HO-1), were significantly higher compared to healthy controls (0.46 ± 0.01; 0.08 ± 0.02; 0.21 ± 0.05 vs 0.18 ± 0.04; 0.02 ± 0.005; 0.035 ± 0.008; respectively, P&lt;0.02). HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased (0.11 ± 0.05; 0.37 ± 0.12, SCAHU and SCA, respectively; P&lt;0.05). In SCA neutrophils, gene expressions of IL-8, IFN-γ, iNOS and HO-1 were significantly higher compared to those of control subjects (0.32 ± 0.07; 0.69 ± 0.19; 0.19 ± 0.06; 0.33 ± 0.09, P=0.02, P=0.025, P&lt;0.05; P=0.027, respectively). Patients on HU therapy demonstrated lower iNOS and higher IL-10 neutrophil gene expressions compared to SCA not on HU therapy (0.038 ± 0.03; 0.72 ± 0.13, P&lt;0.05; P&lt;0.05, respectively). Taken together, data suggest that alterations in the gene expressions and productions of a number of pro-and anti-inflammatory mediators are present in SCA and knowledge of these pathways may be important for identifying novel drug targets for the disease.

scholarly journals Circulating Cell-Free DNA in Sickle Cell Disease: Is It a Potentially Useful Biomarker?

2014 ◽  
Vol 138 (5) ◽  
pp. 678-683 ◽  
Author(s):  
Salah Al-Humood ◽  
Rajaa Zueriq ◽  
Lama Al-Faris ◽  
Rajaa Marouf ◽  
Fahd Al-Mulla
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Plasma Cell ◽  
Sickle Cell Trait ◽  
Healthy Controls ◽  
Cell Disease ◽  
Cell Free Dna ◽  
Free Dna ◽  
Polymerase Chain

Context.—Vascular occlusion in sickle cell disease causes increased levels of plasma cell-free DNA as a result of cell death and tissue damage. Objectives.—This study investigates plasma cell-free DNA concentrations in sickle cell disease patients, and aims at exploring the significance of plasma cell-free DNA as a potential biomarker in predicting its complications. Design.—Plasma cell-free DNA levels were measured using real-time quantitative polymerase chain reaction to quantitatively measure β-globin gene in blood samples from 57 sickle cell disease patients with acute vaso-occlusive crisis, 42 patients in steady state, 16 individuals with sickle cell trait, and 40 healthy controls. Results.—Plasma cell-free DNA level was significantly elevated in samples from patients with acute vaso-occlusive crisis when compared with those in steady state (P = .002), and was significantly higher both in crisis and in steady state when compared with individuals with sickle cell trait and healthy controls (P &lt; .001). There was no difference in cell-free DNA levels between individuals with sickle cell trait and healthy controls. There was no association between plasma cell-free DNA levels and various clinical complications of sickle cell disease and comorbidity. Conclusions.—Plasma cell-free DNA, as quantified by polymerase chain reaction amplification of the β-globin and human telomerase reverse transcriptase genes, is increased in sickle cell disease patients in vaso-occlusive crisis and in steady state compared with individuals with sickle cell trait and healthy controls, and may be used as a tool to diagnose and monitor the sickle cell crisis and differentiate post–packed red cell transfusion sickle cell disease patients from individuals with sickle cell trait.

scholarly journals Pro- and Anti-Inflammatory Cytokines Release in Mice Injected withCrotalus durissus terrificusVenom

2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
A. Hernández Cruz ◽  
S. Garcia-Jimenez ◽  
R. Zucatelli Mendonça ◽  
V. L. Petricevich
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Mediators ◽  
Inflammatory Cytokine ◽  
Time Course ◽  
Dependent Manner ◽  
Blood Biochemical ◽  
Cytokine Balance ◽  
Anti Inflammatory ◽  
Crotalus Durissus ◽  
Anti Inflammatory Cytokine

The effects ofCrotalus durissus terrificusvenom (Cdt) were analyzed with respect to the susceptibility and the inflammatory mediators in an experimental model of severe envenomation. BALB/c female mice injected intraperitoneally presented sensibility to Cdt, with changes in specific signs, blood biochemical and inflammatory mediators. The venom induced reduction of glucose and urea levels and an increment of creatinine levels in serum from mice. Significant differences were observed in the time-course of mediator levels in sera from mice injected with Cdt. The maximum levels of IL-6, NO, IL-5, TNF, IL-4 and IL-10 were observed 15 min, 30 min, 1, 2 and 4 hours post-injection, respectively. No difference was observed for levels of IFN-γ. Taken together, these data indicate that the envenomation by Cdt is regulated both pro- and anti-inflammatory cytokine responses at time-dependent manner. In serum from mice injected with Cdt at the two first hours revealed of pro-inflammatory dominance. However, with an increment of time an increase of anti-inflammatory cytokines was observed and the balance toward to anti-inflammatory dominance. In conclusion, the observation that Cdt affects the production of pro- and anti-inflammatory cytokines provides further evidence for the role played by Cdt in modulating pro/anti-inflammatory cytokine balance.

scholarly journals Cytokine profiles in highly active antiretroviral treatment non-adherent, adherent and naive HIV-1 infected patients in Western Kenya

2021 ◽  
Vol 21 (4) ◽  
pp. 1584-92
Author(s):  
Fauzia Musa ◽  
Nathan Shaviya ◽  
Fidelis Mambo ◽  
Collins Abonyo ◽  
Erick Barasa ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Antiretroviral Treatment ◽  
Healthy Controls ◽  
Highly Active ◽  
Cytokine Balance ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Hiv 1

Background: Cytokines play an important role in signaling the immune system to build an adequate immune responseagainst HIV. HIV distorts the balance between pro and anti-inflammatory cytokines causing viral replication. Highly active antiretroviral treatment (HAART) acts by trying to restore pro and anti-inflammatory cytokine balance. It is not clear how HAART non-adherence influences circulating cytokine levels. This study therefore determined cytokine levels in HAART non-adherent individuals. Methods: This cross-sectional study recruited 163 participants (51 controls, 23 HIV-1+ HAART naive, 28 HAART-adherent6 months, 19 HAART-adherent 12 months and 42 HAART non-adherent). Cytokines were analyzed by ELISA while CD4 T cells determined in 3.0 μl of whole blood using BD FACSCaliburTM and viral load in 0.2ml plasma sample using Abbott Molecular m2000sp sample preparation and m2000rt real-time amplification and detection systems (Abbott MolecularInc., Illinois, USA) according to the manufacturer’s methods. Results: IL-4, IL-6, IL-10, TNF-α and TGF-β were significantly elevated in HIV-1 HAART non-adherent compared withHIV-1 HAART adherent and healthy controls P<0.01. IFN- γ was significantly decreased in HIV-1 HAART non-adherentcompared with HIV-1 HAART adherent and healthy controls P<0.01. TNF-α and TGF-β were significantly reduced in HIV-1 HAART adherent patients at 12 months compared to those at 6 months P<0.01. IL-4 and IL-10 correlated positively withviral load. IL-4, IL-6, IL-10, TNF-α and TGF- β associated inversely with CD4 T cell counts and body mass index (BMI). Conclusion: This study established that HAART adherence is immunologically beneficial to the pro and anti-inflammatory cytokine balance milieu while non-adherence appears to cause alterations in pro and anti-inflammatory cytokines warping the balance in this dichotomy. Keywords: Cytokines; non-adherence; HAART.

scholarly journals Cell-Free Mitochondrial DNA Is Elevated in Sickle Cell Disease Patients, and Serve As a Potential Proinflammatory DAMP

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1068-1068
Author(s):  
Laxminath Tumburu ◽  
Shohini Ghosh-Choudhary ◽  
Emilia Alina Barbu ◽  
Simon Yang ◽  
Lauren D Harrison Ware ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Organ Damage ◽  
Healthy Controls ◽  
Cell Disease ◽  
Cross Sectional ◽  
Healthy Donors

Abstract Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by hemolysis and intermittent acute pain with multi-organ damage. Previously, we showed that acute pain in SCD was associated with >10-fold increases in cell-free DNA (cfDNA) when compared to steady state, that were significantly reduced during hydroxyurea therapy. Apoptosis, necrotic cell death and lysis of intact cells in the blood stream have been proposed as sources of plasma cfDNA. Here, we explored if the cfDNA increases could have a role in inflammation, a constant pathological feature of SCD. cfDNA was extracted using QIAamp MinElute ccfDNA Kit (Qiagen), from the platelet-poor plasma processed within 30 minutes from the blood drawn in EDTA tubes, and analyzed using whole genome sequencing (WGS) and targeted quantitative PCR (qPCR). SCD patients are defined as in acute pain if there is no evident cause other than SCD, for which the patient needs hospitalization, either as in- or outpatient, and is treated with parenteral narcotics. Steady state was defined as the period from at any time 8 weeks prior to or after a crisis. A cross-sectional study of 8 healthy controls and 34 SCD patients (18 steady-state; 16 crisis) mapped WGS reads showed significantly higher proportion of cell-free mitochondrial DNA (cf-mtDNA) compared to nuclear cfDNA (cf-nDNA) in SCD patients compared with healthy controls (Fig 1A: steady-state: 14 fold; crisis: 11 fold; p = 0.0001). We used targeted qPCR to quantify both cf-nDNA and cf-mtDNA in another cross-sectional cohort of 13 healthy controls and 92 patients (72 steady-state, 20 crisis) as well as 18 paired HbSS patients (steady-state and crisis) samples with 10 healthy controls. The nuclear reference genes used were GAPDH and TERT and mitochondrial genes were MT-ND1 and MT-ND6. While cf-nDNA (TERT) was significantly increased (> 3.5 fold, p = 0.0251; Fig 1B) in SCD patients compared with healthy controls only during crises, significantly higher levels of cf-mtDNA over cf-nDNA were observed in SCD patients compared with healthy volunteers in both steady-state and crises (Fig 1C: MT-ND1/GAPDH: steady-state >19 fold, crisis > 8 fold; MT-ND1/TERT: steady-state > 8 fold, crisis > 7 fold; MT-ND6/GAPDH: steady-state > 7 fold, crisis > 3 fold; MT-ND6/TERT: steady-state > 4 fold; crisis > 4 fold; p < 0.05). In the paired samples, cf-nDNA (GAPDH andTERT) was significantly increased (> 3 fold; Fig 1D-E) in crisis compared to steady-state (p < 0.05). The differential increase in cf-mtDNA (cf-mtDNA:cf-nDNA ratio) levels in these patients during crises, were significantly higher compared with healthy controls (Fig 1F: MT-ND1/GAPDH: steady-state >9 fold, crisis > 8 fold; MT-ND1/TERT: steady-state > 8 fold, crisis > 9 fold; MT-ND6/GAPDH: steady-state > 8 fold, crisis > 8 fold; MT-ND6/TERT: steady-state > 8 fold; crisis > 7 fold; p < 0.005). Using confocal microscopy and mitochondrial-specific dyes (MitoTracker Green and TMRM), we show that substantial numbers of red blood cells from SCD patients retain their mitochondria in the circulation. We next explored if the elevated cf-mtDNA in SCD could contribute to its pathophysiology, via activating neutrophils to form neutrophil extracellular traps (NETs), a recognized immunological response in inflammation. Initially, we confirmed that mtDNA can induce NETosis by treating neutrophils from healthy donors with mtDNA isolated from human platelets. mtDNA consistently induced a robust NETs response (N=8) while genomic nuclear DNA did not cause any NETosis. SCD plasma containing high levels of cf-mtDNA also caused a strong NETosis response while plasma from healthy donors did not (N=11). Cytosolic adaptor STING has a central role in sensing of cytosolic double stranded DNA. We sought to determine if the downstream STING-TBK1-IRF3 pathway is associated with the mtDNA-mediated formation of NETs. We inhibited the catalytic activity of the STING downstream effector TBK1 with BX795 prior to treating neutrophils with cf-mtDNA-containing plasma (N=5). The TBK1 inhibition consistently reduced the NETs response by at least 70% confirming that cytosolic DNA sensors are involved in promoting mtDNA-mediated formation of NETs. Our findings suggest that cf-mtDNA induces NETosis contributing to the pathological sterile inflammation in SCD patients. Continual release of these mitochondrial DAMPs in hemolysis may serve as key link between inflammation and organ damage in SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunoregulatory effects of Imuno TF® (transfer factors) on Th1/Th2/Th17/Treg cytokines

2020 ◽  
Author(s):  
Carlos Rocha Oliveira ◽  
Rodolfo Paula Vieira ◽  
Anderson de Oliveira Ferreira ◽  
Any Elisa de Souza Schmidt Gonçalves ◽  
Hudson Polonini
Keyword(s):  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Mrna Levels ◽  
Th2 Cytokines ◽  
Transfer Factors ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Th1 Cytokines ◽  
Anti Inflammatory Cytokine

AbstractTransfer factors are known since 1955 due to their activities on the immune system. Although the reports on the effects on diverse immune mechanisms, their role on Th1, Th2, Th17 and Treg responses was still not described. In this sense, the present work focused on the evaluation of such immune responses. For that, human lymphocytes, and mice thymic, splenic and Peyer’s cells were stimulated with Lipopolysaccharides and Concanavalin A, and then treated with isolated transfer factors (Imuno TF®). The culture medium was harvested and the quantification of Th1 cytokines (IL-2 and IFN-γ), Th2 cytokines (IL-4, IL-5, and IL-13), Th17 cytokine (IL- 17), Treg cytokine (IL-35), inflammatory cytokines (IL-6 and TNF-α), and anti-inflammatory cytokine (IL-10) was performed, as well as the quantification of mRNA levels. Imuno TF® positively regulated Th1 cytokines, while decreased Th2 cytokines. It also increased levels of mRNA and secretion of the anti-inflammatory cytokine IL-10, whereas it reduced levels of mRNA and the secretion of pro-inflammatory cytokines IL-6 and TNF-α. Finally, it reversed the hypersecretion of IL-17 and did not promote significant changes in IL-35 secretion. This highlights the role of Imuno TF® in the regulation of the immune responses.

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