scholarly journals The differential statin effect on cytokine production of monocytes or macrophages is mediated by differential geranylgeranylation-dependent Rac1 activation

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Hang Fu ◽  
Mohamad Alabdullah ◽  
Julia Großmann ◽  
Florian Spieler ◽  
Reem Abdosh ◽  
...  
Keyword(s):  
Cholesterol Synthesis ◽  
Cytokine Production ◽  
Inflammatory Diseases ◽  
Mevalonic Acid ◽  
M2 Macrophage ◽  
Cd163 Expression ◽  
Monocytes And Macrophages ◽  
Factor Α ◽  
Functional Capacities ◽  
Interfering Rna

AbstractMonocytes and macrophages contribute to pathogenesis of various inflammatory diseases, including auto-inflammatory diseases, cancer, sepsis, or atherosclerosis. They do so by production of cytokines, the central regulators of inflammation. Isoprenylation of small G-proteins is involved in regulation of production of some cytokines. Statins possibly affect isoprenylation-dependent cytokine production of monocytes and macrophages differentially. Thus, we compared statin-dependent cytokine production of lipopolysaccharide (LPS)-stimulated freshly isolated human monocytes and macrophages derived from monocytes by overnight differentiation. Stimulated monocytes readily produced tumor necrosis factor-α, interleukin-6, and interleukin-1β. Statins did not alter cytokine production of LPS-stimulated monocytes. In contrast, monocyte-derived macrophages prepared in the absence of statin lost the capacity to produce cytokines, whereas macrophages prepared in the presence of statin still produced cytokines. The cells expressed indistinguishable nuclear factor-kB activity, suggesting involvement of separate, statin-dependent regulation pathways. The presence of statin was necessary during the differentiation phase of the macrophages, indicating that retainment-of-function rather than costimulation was involved. Reconstitution with mevalonic acid, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate blocked the retainment effect, whereas reconstitution of cholesterol synthesis by squalene did not. Inhibition of geranylgeranylation by GGTI-298, but not inhibition of farnesylation or cholesterol synthesis, mimicked the retainment effect of the statin. Inhibition of Rac1 activation by the Rac1/TIAM1-inhibitor NSC23766 or by Rac1-siRNA (small interfering RNA) blocked the retainment effect. Consistent with this finding, macrophages differentiated in the presence of statin expressed enhanced Rac1-GTP-levels. In line with the above hypothesis that monocytes and macrophages are differentially regulated by statins, the CD14/CD16-, merTK-, CX3CR1-, or CD163-expression (M2-macrophage-related) correlated inversely to the cytokine production. Thus, monocytes and macrophages display differential Rac1-geranylgeranylation-dependent functional capacities, that is, statins sway monocytes and macrophages differentially.

scholarly journals Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines

2019 ◽  
Vol 20 (3) ◽  
pp. 459 ◽  
Author(s):  
Leila Kheirandish-Gozal ◽  
David Gozal
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Inflammatory Diseases ◽  
Sleep Apnea Syndrome ◽  
Special Focus ◽  
Normal Body Mass Index ◽  
Low Grade ◽  
Obstructive Sleep ◽  
Inflammatory Processes ◽  
Factor Α

Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates. In adult patients, excessive daytime sleepiness (EDS) is the most frequent symptom leading to clinical referral for evaluation and treatment, but classic EDS features are less likely to be reported in children, particularly among those with normal body-mass index. The cumulative evidence collected over the last two decades supports a conceptual framework, whereby sleep-disordered breathing in general and more particularly OSAS should be viewed as low-grade chronic inflammatory diseases. Accordingly, it is assumed that a proportion of the morbid phenotypic signature in OSAS is causally explained by underlying inflammatory processes inducing end-organ dysfunction. Here, the published links between OSAS and systemic inflammation will be critically reviewed, with special focus on the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), since these constitute classical prototypes of the large spectrum of inflammatory molecules that have been explored in OSAS patients.

scholarly journals Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 868
Author(s):  
Fabiana Albani Zambuzi ◽  
Priscilla Mariane Cardoso-Silva ◽  
Ricardo Cardoso Castro ◽  
Caroline Fontanari ◽  
Flavio da Silva Emery ◽  
...  
Keyword(s):  
Immune Response ◽  
Hematological Malignancies ◽  
M2 Macrophage ◽  
M2 Polarization ◽  
Tnf Α ◽  
Monocytes And Macrophages ◽  
Ifn Γ ◽  
And Function ◽  
The Impact

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.

scholarly journals Cholesterol synthesis in rat liver peroxisomes. Conversion of mevalonic acid to cholesterol.

1987 ◽  
Vol 262 (36) ◽  
pp. 17420-17425 ◽  
Author(s):  
S L Thompson ◽  
R Burrows ◽  
R J Laub ◽  
S K Krisans
Keyword(s):  
Rat Liver ◽  
Cholesterol Synthesis ◽  
Mevalonic Acid ◽  
Liver Peroxisomes

scholarly journals Nepetoidin B from Salvia plebeia R. Br. Inhibits Inflammation by Modulating the NF-κB and Nrf2/HO-1 Signaling Pathways in Macrophage Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1208
Author(s):  
Mina Kim ◽  
Ji Yeong Kim ◽  
Hee Sun Yang ◽  
Jeong-Sook Choe ◽  
In Guk Hwang
Keyword(s):  
Defense Mechanisms ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Treated Group ◽  
Raw 264.7 Cells ◽  
Resonance Spectroscopy ◽  
Raw 264.7 ◽  
Related Factor ◽  
Anti Inflammatory ◽  
Factor Α

Salvia plebeia has been used to treat a variety of inflammatory diseases, as well as colds and bronchitis. Macrophages have antioxidant defense mechanisms to cope with the intracellular reactive oxygen species (ROS) produced as part of the immune response. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway in inflamed macrophages is an appealing target due to its protective effect against ROS-induced cell damage. In this study, nepetoidin B (NeB) was first isolated from S. plebeia and identified by nuclear magnetic resonance spectroscopy. NeB reduced pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β) in LPS-activated RAW 264.7 cells by inhibiting the NF-κB signaling pathway. In the NeB-treated group, catalase and superoxide dismutase levels were significantly higher, and ROS expression decreased. By activating Nrf2 signaling, NeB enhanced HO-1 expression. Furthermore, when the cells were pretreated with tin protoporphyrin (an HO-1 inhibitor), the anti-inflammatory effects of NeB were reduced. Therefore, NeB may activate the Nrf2/ HO-1 pathway. These results reveal the NeB isolated from S. plebeia exerts anti-inflammatory effects by modulating NF-κB signaling and activating the Nrf2/HO-1 pathway in LPS-stimulated RAW 264.7 cells.

scholarly journals Acute systemic experimental inflammation does not reduce human odor identification performance

2021 ◽  
Author(s):  
A Tognetti ◽  
G Sarolidou ◽  
J Lasselin ◽  
M Lekander ◽  
M J Olsson ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Inflammatory Diseases ◽  
Placebo Treatment ◽  
Olfactory Dysfunction ◽  
High Dose ◽  
Common Symptom ◽  
Identification Performance ◽  
Double Blind ◽  
Olfactory Identification ◽  
Factor Α

Abstract Olfactory dysfunction is a common symptom of various diseases but the underlying pathophysiology has not been fully understood. Evidence from both animal and human studies suggests that local inflammation of the olfactory epithelium is linked to olfactory dysfunction. However, whether systemic inflammation causes olfactory dysfunction is yet to be determined. In the present behavioral study, we set out to test whether acute systemic inflammation impairs olfactory identification performance by inducing a transient and controlled state of systemic inflammation using an experimental endotoxemia model. We treated young, otherwise healthy, participants (N=20) with a relatively high dose (2.0 ng/kg) of lipopolysaccharide (LPS) and a placebo treatment in a double-blind within-subject design, and assessed participants’ ability to identify odors using the MONEX-40, a reliable method for experimental assessment of odor ID ability in healthy and young individuals. Our results show that olfactory identification performance was not affected by the acute systemic inflammation triggered by the injection of LPS. Moreover, no associations were found between the change of olfactory performance followed by LPS injection and levels of circulating pro-inflammatory cytokines (interleukin-6, interleukin-8, and tumor necrosis factor-α). Because experimental LPS-induced systemic inflammation does not affect olfactory identification performance, our findings suggest that chronic, rather than transient, systemic inflammation is a more likely mechanism to explore in order to explain the olfactory deficits observed in inflammatory diseases.

scholarly journals Inflammatory Mediators and Insulin Resistance in Obesity: Role of Nuclear Receptor Signaling in Macrophages

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Lucía Fuentes ◽  
Tamás Rőszer ◽  
Mercedes Ricote
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Liver Steatosis ◽  
Visceral Obesity ◽  
M2 Macrophage ◽  
Low Grade ◽  
The Impact

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.

scholarly journals Cytokine profile after rubella vaccine inoculation: evidence of the immunosuppressive effect of vaccination

2003 ◽  
Vol 12 (4) ◽  
pp. 203-207 ◽  
Author(s):  
Alexander L. Pukhalsky ◽  
Galina V. Shmarina ◽  
Maria S. Bliacher ◽  
Irina M. Fedorova ◽  
Anna P. Toptygina ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cytokine Production ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumour Necrosis Factor Α ◽  
Lymphocyte Response ◽  
Rubella Vaccine ◽  
Live Virus ◽  
Factor Α ◽  
Necrosis Factor

Background:Immunization with live virus vaccines may cause an immunosuppression with lymphopaenia, impaired cytokine production and defective lymphocyte response to mitogenes. These abnormalities were described in subjects vaccinated against measles. This study was performed to analyse the host immune response related to immunosuppression in subjects vaccinated with live attenuated rubella vaccine.Methods:Eighteen schoolgirls, aged 11-13 years, were vaccinated with live attenuated rubella vaccine Rudivax®. Before immunization, and 7 and 30 days after, peripheral blood was collected. Cellular fractions were subjected to flow cytometric analysis, and the lymphocyte response to phytohaemagglutinin was investigated. Plasma samples were analysed for cytokines (interleukin (IL)-4, IL-10, tumour necrosis factor-α, and interferon-γ) by enzyme-linked immunosorbent assay techniques.Results:On day 7 after vaccination, the number of each lymphocyte subset was decreased; however, only for CD3 and CD4 lymphocytes has a significant reduction been shown. On the contrary, tumour necrosis factor-α and IL-10 levels markedly increased and amounted to its maximum on day 30. Simultaneously, a significant reduction in plasma interferon-γand a profound decrease of the lymphocyte response to phytohaemagglutinin were shown. The changes were accompanied with marked elevation of plasma IL-4.Conclusions:Our data indicate that the vaccination with live attenuated rubella vaccine results in moderate but sustained immune disturbance. The signs of immunosuppression, including defective lymphocyte response to mitogene and impaired cytokine production, may persist for at least 1 month after vaccination.

scholarly journals Effect of pregnancy hormone mixtures on cytokine production and surface marker expression in naïve and LPS-activated THP-1 differentiated monocytes/macrophages

2019 ◽  
Vol 26 (2) ◽  
pp. 84-96
Author(s):  
María Isabel Mendoza-Cabrera ◽  
Rosa-Elena Navarro-Hernández ◽  
Anne Santerre ◽  
Pablo Cesar Ortiz-Lazareno ◽  
Ana Laura Pereira-Suárez ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cytokine Production ◽  
Immune Cell ◽  
Surface Marker ◽  
Independent Manner ◽  
Surface Marker Expression ◽  
Monocytes And Macrophages ◽  
Marker Expression ◽  
Activated Monocytes ◽  
In Pregnancy

In pregnancy, maternal monocytes and macrophages acquire a specific phenotype that enables them to maintain immune tolerance and facilitate hormone–immune cell interactions, which are necessary for gestational progression. The aim of this study was to determine the effect of pregnancy hormone mixtures of the first and third trimesters on both resting and activated monocytes and macrophages. Pregnancy hormone levels (cortisol, estradiol, progesterone, and prolactin) were quantified at the first and third trimesters. The average of the levels obtained was used to prepare two mixtures of synthetic hormones: low and high. These mixtures were then used to stimulate THP-1 monocytes and macrophages, resting or activated with LPS. Cytokine production in the culture supernatants and surface marker expression (CD14, CD86, and CD163) were evaluated by ELISA and flow cytometry, respectively. We found that the hormones modulated the pro-inflammatory response of THP-1 cells, LPS-activated monocytes, and macrophages, inducing high levels of IL-10 and low levels of IL-8, IL-1-β, and IL-6. All hormone stimulation increased the CD163 receptor in both resting and LPS-activated monocytes and macrophages in a dose-independent manner, unlike CD14 and CD86. Pregnancy hormones promote the expression of the markers associated with the M2-like phenotype, modulating their pro-inflammatory response. This phenotype regulation by hormones could be a determinant in pregnancy.

scholarly journals An Exaggerated Monocyte-Derived Cytokine Response to Candida Hyphae in Patients With Recurrent Vulvovaginal Candidiasis

2020 ◽  
Author(s):  
Diletta Rosati ◽  
Mariolina Bruno ◽  
Martin Jaeger ◽  
Bart-Jan Kullberg ◽  
Frank van de Veerdonk ◽  
...  
Keyword(s):  
Immune Response ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Adaptive Immune Response ◽  
Vulvovaginal Candidiasis ◽  
T Helper 1 ◽  
Recurrent Vulvovaginal Candidiasis ◽  
Tnf Α ◽  
Group A ◽  
Factor Α

Abstract Background Recurrent vulvovaginal candidiasis (RVVC) affects up to 8% of women. The immunopathogenesis is poorly understood but it has been suggested that RVVC might be due to dysregulated innate immune response. The aim of this study was to compare cytokine profiles in stimulated primary mononuclear cells (PBMCs) from RVVC and healthy individuals. Methods PBMCs isolated from RVVC patients (n = 24) and healthy volunteers (n = 30) were stimulated with unspecific and pathogen-specific antigens. Cytokine production was assessed after 24 hours, 48 hours, and 7 days using ELISA. Results No significant differences in cytokine production were found in T helper 1 (Th1), Th2, and Th17 immunity in response to both unspecific and pathogen-specific stimulations. Tumor necrosis factor-α (TNF-α) production in response to C. albicans hyphae was significantly higher in patients than controls and within the patient group, a significant positive correlation was found between interleukin-1β (IL-1β) and both TNF-α and IL-6. Both IL-1β/IL-1Ra and TNF-α/IL-10 ratios in Candida hyphae-stimulated PBMCs were significantly higher in patients than controls. Conclusions Women affected by RVVC showed increased monocytes-derived cytokine production, which might contribute to an exaggerated vaginal immune response to Candida hyphae. RVVC patients show no defective Th-dependent adaptive immune response upon Candida stimulation.

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