scholarly journals Propofol Suppresses Proinflammatory Cytokine Production by Increasing ABCA1 Expression via Mediation by the Long Noncoding RNA LOC286367

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Xin Ma ◽  
Teng Wang ◽  
Zhen-Long Zhao ◽  
Yu Jiang ◽  
Shu Ye
Keyword(s):  
Proinflammatory Cytokine ◽  
Noncoding Rna ◽  
Cytokine Production ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Proinflammatory Cytokine Production ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Binding Cassette Transporter ◽  
Abca1 Expression ◽  
Necrosis Factor

We previously reported that propofol upregulated the expression of ATP-binding cassette transporter subfamily A member 1 (ABCA1) via peroxisome proliferator-activated receptor gamma/liver X receptor in macrophage-derived foam cells. Here, we provide evidence that in addition to inducing ABCA1 expression, propofol represses proinflammatory cytokine production by increasing ABCA1 expression in a LOC286367-dependent manner. Western blot analysis showed that ABCA1 expression was elevated in macrophages by propofol treatment and this effect was markedly reduced by LOC286367 overexpression. Moreover, propofol treatment downregulated the production of the proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon gamma in lipopolysaccharide-stimulated macrophages by enhancing ABCA1 expression. Notably, propofol achieved this effect in a LOC286367-dependent manner. To the best of our knowledge, this is the first report of the mechanism in which propofol represses proinflammatory cytokine production mediated by ABCA1.

scholarly journals Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia

2020 ◽  
Vol 295 (10) ◽  
pp. 3099-3114
Author(s):  
Nina E. Murugina ◽  
Anna S. Budikhina ◽  
Yulia A. Dagil ◽  
Polina V. Maximchik ◽  
Lyudmila S. Balyasova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Necrosis Factor ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Cytokine Production ◽  
Glucose Starvation ◽  
Proinflammatory Cytokine Production ◽  
Unfolded Protein ◽  
Protein Response ◽  
Necrosis Factor

Upon activation with pathogen-associated molecular patterns, metabolism of macrophages and dendritic cells is shifted from oxidative phosphorylation to aerobic glycolysis, which is considered important for proinflammatory cytokine production. Fragments of bacterial peptidoglycan (muramyl peptides) activate innate immune cells through nucleotide-binding oligomerization domain (NOD) 1 and/or NOD2 receptors. Here, we show that NOD1 and NOD2 agonists induce early glycolytic reprogramming of human monocyte-derived macrophages (MDM), which is similar to that induced by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide. This glycolytic reprogramming depends on Akt kinases, independent of mTOR complex 1 and is efficiently inhibited by 2-deoxy-d-glucose (2-DG) or by glucose starvation. 2-DG inhibits proinflammatory cytokine production by MDM and monocyte-derived dendritic cells activated by NOD1 or TLR4 agonists, except for tumor necrosis factor production by MDM, which is inhibited initially, but augmented 4 h after addition of agonists and later. However, 2-DG exerts these effects by inducing unfolded protein response rather than by inhibiting glycolysis. By contrast, glucose starvation does not cause unfolded protein response and, in normoxic conditions, only marginally affects proinflammatory cytokine production triggered through NOD1 or TLR4. In hypoxia mimicked by treating MDM with oligomycin (a mitochondrial ATP synthase inhibitor), both 2-DG and glucose starvation strongly suppress tumor necrosis factor and interleukin-6 production and compromise cell viability. In summary, the requirement of glycolytic reprogramming for proinflammatory cytokine production in normoxia is not obvious, and effects of 2-DG on cytokine responses should be interpreted cautiously. In hypoxia, however, glycolysis becomes critical for cytokine production and cell survival.

scholarly journals Aeromonas sobria Induces Proinflammatory Cytokines Production in Mouse Macrophages via Activating NLRP3 Inflammasome Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Zhang ◽  
Zhixing Li ◽  
Haitao Yang ◽  
Guanglu Wang ◽  
Gang Liu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Dependent Manner ◽  
Proinflammatory Cytokine Production ◽  
Expression Levels ◽  
Caspase 1 ◽  
Aeromonas Sobria ◽  
Ldh Release

Aeromonas sobria, a common conditional pathogenic bacteria, is widely distributed in the environment and causes gastroenteritis in humans or septicemia in fish. Of all Aeromonas species, A. sobria is the most frequently isolated from human infections especially in immunocompromised subjects. Innate immunity is the first protection system of organism to resist non-specific pathogens invasion; however, the immune response process of hosts against A. sobria infection re\mains unexplored. The present study established an A. sobria infection model using primary mouse peritoneal macrophages (PMφs). The adherence and cytotoxicity of A. sobria on PMφs were determined by May-Grünwald Giemsa staining and LDH release measurement. Pro-inflammatory cytokine expression levels were measured using qPCR, western blotting, and ELISA methods. We also investigated the levels of ASC oligomerization and determined the roles of active caspase-1 in IL-1β secretion through inhibition assays and explored the activated pattern recognition receptors through immunofluorescence. We further elucidated the roles of activated inflammasome in regulating the host’s inflammatory response through inhibition combined with ELISA assays. Our results showed that A. sobria induced lytic cell death and LDH release, whereas it had no adhesive properties on PMφs. A. sobria triggered various proinflammatory cytokine transcription level upregulation, and IL-1β occupied the highest levels. The pro-IL-1β protein expression levels increased in a dose-dependent manner with MOI ranging from 1 to 100. This process was regulated by ASC-dependent inflammasome, which cleavage pro-IL-1β into active IL-1β p17 with activated caspase-1 p20. Meanwhile, the expression levels of NLRP3 receptor significantly increased, location analysis revealed puncta-like surrounding nuclear, and inhibition of NLRP3 inflammasome downregulated caspase-1 activation and IL-1β secretion. Blocking of NLRP3 inflammasome activation through K+ efflux and cathepsin B or caspase approaches downregulated A. sobria–induced proinflammatory cytokine production. Overall, these data indicated that A. sobria induced proinflammatory cytokine production in PMφs through activating NLRP3 inflammasome signaling pathways.

scholarly journals 862 Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A903-A903
Author(s):  
Justin Kenkel ◽  
Po Ho ◽  
Sameera Kongara ◽  
Karla Henning ◽  
Cindy Kreder ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Antigen Processing ◽  
Cytokine Production ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Costimulatory Molecule ◽  
Mouse Tumor ◽  
Dependent Manner ◽  
Proinflammatory Cytokine Production

BackgroundTumor-associated macrophages (TAMs) are an abundant immune cell population in most cancers that support tumor progression through their immunosuppressive effects. We discovered that TAMs express the pattern recognition receptor Dectin-2 (Clec4n/CLEC6A), an activating C-type lectin receptor (CLR) that binds to high-mannose glycans on fungi and other microbes and induces protective immune responses against infectious disease. Dectin-2 is selectively expressed by myeloid cells, and upon ligation mediates enhanced phagocytosis, antigen processing and presentation, and proinflammatory cytokine production. Given these properties, we evaluated the therapeutic potential of targeting Dectin-2 using naturally derived ligands. We also generated human Dectin-2-targeted agonistic antibodies capable of robustly activating immunosuppressive ”M2” or TAM-like macrophages.MethodsDectin-2 expression was assessed by flow cytometry, immunohistochemistry, and using public databases. Mouse and human monocytes were differentiated into macrophages using recombinant cytokines or tumor-conditioned media, and stimulation was measured following overnight incubation with Dectin-2 ligands or antibodies. Mouse tumor cell lines were implanted into syngeneic hosts and mice were treated with mannan derived from S. cerevisiae via IT or IV administration.ResultsDectin-2 gene expression is minimal in normal human tissues but elevated across many tumor types, including breast, colon, lung, and kidney cancers. Dectin-2 is strongly expressed by macrophages differentiated in vitro and on primary TAMs. The fungal Dectin-2 ligand mannan stimulated proinflammatory cytokine production (e.g. TNFalpha) and costimulatory molecule expression (e.g. CD86) by macrophages in a Dectin-2-dependent manner. Treatment of tumor-bearing mice with mannan mediated tumor regression in multiple syngeneic tumor models, with high rates of tumor clearance in the MB49 bladder cancer model. These effects were Dectin-2 dependent, as efficacy was not observed when a Dectin-2-blocking antibody was co-administered or in knockout mice lacking Dectin-2 signaling components. Furthermore, depletion of either macrophages or T cells impaired efficacy, suggesting that Dectin-2-stimulated TAMs augment anti-tumor T cell responses. Based on these data, we developed novel Dectin-2 targeted agonist antibodies capable of activating human ”M2” or TAM-like macrophages in vitro to produce an array of proinflammatory cytokines and chemokines akin to tumor-destructive ”M1” macrophages.ConclusionsThe data presented demonstrate the therapeutic potential of targeting Dectin-2 using natural ligands or agonistic antibodies as a novel pan-cancer approach for myeloid cell-directed tumor immunotherapy.Ethics ApprovalAll animal studies were performed in accordance with Institutional Animal Care and Use Committee (IACUC)-approved protocols.

scholarly journals The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis

2021 ◽  
Author(s):  
Xian-Hui Dong ◽  
Zhi-Feng Lu ◽  
Chun-Min Kang ◽  
Xue-Heng Li ◽  
Kim E. Haworth ◽  
...  
Keyword(s):  
Ion Transport ◽  
Long Noncoding Rna ◽  
Proinflammatory Cytokine ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Cytokine Production ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Cholesterol Homeostasis ◽  
Proinflammatory Cytokine Production

Objective: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na + /K + -ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na + /K + -ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. Conclusions: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target.

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