scholarly journals Selective Biological Responses of Phagocytes and Lungs to Purified Histones

2017 ◽  
Vol 9 (3) ◽  
pp. 300-317 ◽  
Author(s):  
Fatemeh Fattahi ◽  
Jamison J. Grailer ◽  
Hope Lu ◽  
Rachel S. Dick ◽  
Michella Parlett ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Polymorphonuclear Neutrophils ◽  
Cell Swelling ◽  
Cytokine Release ◽  
Inhibitory Effects ◽  
Lactate Dehydrogenase Release ◽  
Biological Responses ◽  
Proinflammatory Responses ◽  
Mouse Lungs

Histones invoke strong proinflammatory responses in many different organs and cells. We assessed biological responses to purified or recombinant histones, using human and murine phagocytes and mouse lungs. H1 had the strongest ability in vitro to induce cell swelling independent of requirements for toll-like receptors (TLRs) 2 or 4. These responses were also associated with lactate dehydrogenase release. H3 and H2B were the strongest inducers of [Ca2+]i elevations in phagocytes. Cytokine and chemokine release from mouse and human phagocytes was predominately a function of H2A and H2B. Double TLR2 and TLR4 knockout (KO) mice had dramatically reduced cytokine release induced in macrophages exposed to individual histones. In contrast, macrophages from single TLR-KO mice showed few inhibitory effects on cytokine production. Using the NLRP3 inflammasome protocol, release of mature IL-1β was predominantly a feature of H1. Acute lung injury following the airway delivery of histones suggested that H1, H2A, and H2B were linked to alveolar leak of albumin and the buildup of polymorphonuclear neutrophils as well as the release of chemokines and cytokines into bronchoalveolar fluids. These results demonstrate distinct biological roles for individual histones in the context of inflammation biology and the requirement of both TLR2 and TLR4.

scholarly journals In vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

2020 ◽  
Author(s):  
Clarissa S. Santoso ◽  
Zhaorong Li ◽  
Jaice T. Rottenberg ◽  
Xing Liu ◽  
Vivian X. Shen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Lavage Fluid ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Peripheral Blood Mononuclear ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractTreatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drug combinations on inflammatory cytokine production in peripheral blood mononuclear cells, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.

Apoptosis and cytokine release are biological responses mediated by recombinant mistletoe lectin in vitro

1997 ◽  
Vol 33 ◽  
pp. S35 ◽  
Author(s):  
B. Moeckel ◽  
T. Schwarz ◽  
J. Eck ◽  
M. Langer ◽  
H. Zinke ◽  
...  
Keyword(s):  
Mistletoe Lectin ◽  
Cytokine Release ◽  
Biological Responses

scholarly journals Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract

2016 ◽  
Vol 198 (6) ◽  
pp. 964-972 ◽  
Author(s):  
Dennis J. Horvath ◽  
Ashay S. Patel ◽  
Ahmad Mohamed ◽  
Douglas W. Storm ◽  
Chandra Singh ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Host Pathogen Interactions ◽  
Sugar Moiety ◽  
Severity Of Disease ◽  
O Antigen ◽  
Host Pathogen ◽  
Proinflammatory Responses

ABSTRACTUrinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitationin vitroby clinical isolates of uropathogenicEscherichia coli(UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responsesin vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection.IMPORTANCEThe specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed usingin vitromodels of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production.

Inhibitory effects of wild bitter melon leaf extract on Propionibacterium acnes-induced skin inflammation in mice and cytokine production in vitro

2015 ◽  
Vol 6 (8) ◽  
pp. 2550-2560 ◽  
Author(s):  
Wen-Cheng Huang ◽  
Tsung-Hsien Tsai ◽  
Ching-Jang Huang ◽  
You-Yi Li ◽  
Jong-Ho Chyuan ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Cytokine Production ◽  
Propionibacterium Acnes ◽  
Skin Inflammation ◽  
Bitter Melon ◽  
Inhibitory Effects

Propionibacterium acnes is a key pathogen involved in acne inflammation.

scholarly journals Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

2001 ◽  
Vol 45 (10) ◽  
pp. 2798-2806 ◽  
Author(s):  
H. Abdelghaffar ◽  
D. Vazifeh ◽  
M. T. Labro
Keyword(s):  
Protein Kinase ◽  
Transport System ◽  
Polymorphonuclear Neutrophils ◽  
Inhibitory Effects ◽  
Kinase C ◽  
Carrier Mediated Transport ◽  
Erythromycin A ◽  
Active Transport System ◽  
External Ph

ABSTRACT We analyzed the cellular accumulation of two new fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils (PMN) in vitro. Both compounds were rapidly taken up by PMN, with a cellular-to-extracellular concentration ratio (C/E) of about 141 (HMR 3562) and 117 (HMR 3787) at 5 min, and this was followed by a plateau at 60 to 180 min, with a C/E of >300 at 180 min. Both ketolides were mainly located in PMN granules (about 75%) and egressed slowly from loaded cells (about 40% at 60 min), owing to avid reuptake. Uptake was moderately sensitive to external pH, and activation energy was also moderate (about 70 kJ/mol). As with other macrolides and ketolides, the existence of an active transport system was suggested by (i) the strong interindividual variability in uptake kinetics, suggesting variability in the number or activity of a transport protein; (ii) the saturation kinetics characteristic of a carrier-mediated transport system (V max, about 2,300 ng/2.5 × 106 PMN/5 min; Km , about 50 μg/ml); (iii) the inhibitory effects of Ni2+ (a blocker of the Na+-Ca2+ exchanger), phorbol myristate acetate (a protein kinase C activator), and H89 (a protein kinase A inhibitor). Although these two ketolides are more related to HMR 3647 (telithromycin), it is interesting that the presence of a fluoride gave these molecules a cellular pharmacokinetics more like those of HMR 3004 than those of HMR 3647. The macrolide transport system has not been yet elucidated, but our data confirm that, despite variations in chemical structure, all erythromycin A derivatives share a transmembrane transport system.

Effects of Zotarolimus (ABT-578), Sirolimus, Paclitaxel and Dexamethasone on Cytokine Production by Human Monocytes In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3866-3866
Author(s):  
Lanlan Li ◽  
Sandra E. Burke ◽  
Matthew M. Mack
Keyword(s):  
Cytokine Production ◽  
Coronary Intervention ◽  
Human Monocytes ◽  
Cytokine Release ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Percutaneous Coronary ◽  
Drug Eluting ◽  
Necrosis Factor

Abstract Introduction: Percutaneous coronary intervention (PCI) and stenting are common therapies used to mitigate symptomatic coronary artery stenosis. These mechanical procedures are invariably associated with local and systemic inflammation, including activation and cytokine release from monocytes/macrophages, which are major stimuli for smooth muscle cell proliferation, migration and restenosis. Drug-eluting stents (DES) may potentially attenuate this inflammatory response, provided that the drug has antiinflammatory potency. This study was conducted to determine the effects of common DES agents on the generation of proinflammatory cytokines by stimulated human monocytes in vitro. Methods: The production of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) by LPS-stimulated monocytes was determined by ELISA after exposure to either zotarolimus (ABT-578), sirolimus, dexamethasone or paclitaxel. Results: The results showed that zotarolimus (ABT-578) and sirolimus were potent inhibitors of MCP-1 production (IC50 = 2.6 ± 0.2 and 5.9 ± 1.9 nM, respectively). Dexamethasone also inhibited MCP-1 production, but it was less potent (IC50 = 626.9 ± 60.8 nM). TNF-a and IL-6 production were dose-dependently inhibited by dexamethasone (IC50 = 5.5 ± 0.2 and 13.0 ± 3.7 nM, respectively). However, the production of neither cytokine was significantly inhibited by exposure to zotarolimus or sirolimus. Stimulated monocytes were not affected by paclitaxel; cytokine release after exposure to paclitaxel was no different from controls. Conclusions: Zotarolimus and sirolimus are potent inhibitors of MCP-1 secretion by stimulated monocytes in culture. Dexamethasone is a less potent inhibitor of MCP-1 secretion, but effectively inhibits the release of TNF-a and IL-6. The anti-restenotic effect of these agents may, in part, be due to their potent antiinflammatory properties.

Inhibitory effects of CuInS2 and CdTe nanoparticles on macrophage cytokine production and phagocytosis in vitro

2019 ◽  
Vol 127 ◽  
pp. 50-57 ◽  
Author(s):  
Cai-Xia Yao ◽  
Tian-Yang Lin ◽  
Yi-Long Su ◽  
Hui Zou ◽  
Zheng-Yu Yan ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Inhibitory Effects ◽  
Cdte Nanoparticles ◽  
Macrophage Cytokine
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