• inflammation
• innovative biotechnologies
• precision medicine
• skin
• tumor necrosis factor-alpha

• Tumor Necrosis Factor-alpha/metabolism
• Humans
• Skin/metabolism
• Skin/pathology
• Skin/radiation effects
• Animals
• Skin Diseases/metabolism
• Skin Diseases/etiology
• Skin Diseases/pathology
• Inflammation/metabolism
• Inflammation/pathology

• Linea D1 Università Cattolica del Sacro Cuore

• antiphospholipid syndrome
• autoimmunity
• chronic leg ulcer
• juvenile loss of teeth
• moesin protein
• thyroiditis
• whole exome sequencing

• Antiphospholipid Syndrome
• Cryoglobulins
• Hashimoto Disease/genetics
• Humans
• Lupus Coagulation Inhibitor
• Male
• Microfilament Proteins
• Phenotype
• RNA, Messenger
• Tooth Loss

• Nemzeti Kutatási, Fejlesztési és Innovaciós Alap

Acetylcholine (ACh) regulates inflammation via α7 nicotinic acetylcholine receptor (α7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF-κB onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of α7 nAChR and AChE was found in macrophages, suggesting the potential interaction of α7 nAChR and AChE. Besides, immunoprecipitation showed a close association of α7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with α7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses.

• ACh, acetylcholine
• AChE
• AChE, acetylcholinesterase
• BChE, butyrylcholinesterase
• CAP pathway, cholinergic anti-inflammatory pathway
• CDC42, cell division cycle
• ChAT, choline acetyltransferase
• Cholinergic anti-inflammatory pathway
• DPZ, donepezil
• GAL, galantamine hydrobromide
• IL, interleukin
• LPS, lipopolysaccharides
• MLA, methyllycaconitine citrate salt
• MMP, matrix metalloproteinase
• Macrophage
• NF-κB, nuclear factor-κB
• PHA, PHA-543613
• PRiMA, proline-rich membrane anchor
• TNF-α, tumor necrosis factor α
• nAChR, nicotinic AChR
• α7 nAChR

• Anti-inflammation
• COX-2
• IL-1 β
• IL-10
• Inflammatory cytokines
• Molecular docking
• Pyrazolopyridines

• Animals
• Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis
• Anti-Inflammatory Agents, Non-Steroidal/chemistry
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Cell Line
• Cell Survival/drug effects
• Cyclooxygenase 2/metabolism
• Cyclooxygenase 2 Inhibitors/chemical synthesis
• Cyclooxygenase 2 Inhibitors/chemistry
• Cyclooxygenase 2 Inhibitors/pharmacology
• Cytokines/antagonists & inhibitors
• Cytokines/biosynthesis
• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Lipopolysaccharides/antagonists & inhibitors
• Lipopolysaccharides/pharmacology
• Macrophages/drug effects
• Macrophages/metabolism
• Mice
• Molecular Docking Simulation
• Molecular Structure
• Pyrazoles/chemistry
• Pyrazoles/pharmacology
• Pyridines/chemistry
• Pyridines/pharmacology
• Structure-Activity Relationship

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.

Gram-negative bacterial lipopolysaccharide (LPS) is both a central mediator of sepsis and a canonical inducer of acute inflammation via Toll-like receptor 4 (TLR4). Sepsis involves the systemic spillover of inflammation that normally remains localized in individual organs. The goal of this study was to gain insights into 1) early vs. later drivers of LPS-induced inflammation in various compartments, and 2) the systemic spillover from affected organs vs. local production of inflammatory mediators in the blood. This study involved a large number of data points on the dynamics of inflammatory mediators at the protein level, data-driven computational modeling of principal characteristics and cross-correlations, and validation of key hypotheses. In addition to verifying key mechanisms in LPS/TLR4-driven acute inflammation, this approach yielded key insights into the progression of inflammation across tissues, and also suggested the presence of TLR4-independent pathways (especially in the gut). This is, to our knowledge, the first study examining the dynamic evolution of some key inflammatory mediators and their interactions with each other in both the systemic circulation and within a number of targeted parenchymal organs in mice.

The innate immune response is a central process that is activated during pathogenic infection in order to maintain physiological homeostasis. It is well known that dexamethasone (Dex), a synthetic glucocorticoid, is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides (LPS). Nevertheless, the extent to which the functional groups of Dex control the excessive activation of inflammatory reactions remains unknown. Furthermore, importantly, the role of Dex in the innate immune response remains unclear. Here we explore the mechanism of LPS-induced TNF-α secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-α (TNF-α)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-α that allows its secretion. We further demonstrate that the 11-hydroxyl and 21-hydroxyl groups of Dex are the main groups that are involved in reducing LPS-induced TNF-α secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-α secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity.

• TNF-α secretion
• dexamethasone
• innate immunity
• p38 MAPK signaling
• tumor necrosis factor-α (TNF-α)-converting enzyme

Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). In addition, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in upregulation or downregulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.

• autoimmune diseases
• regulatory T cells
• tumor necrosis factor receptor 1
• tumor necrosis factor receptor 2
• tumor necrosis factor α

• NRF2
• cytokines
• emotions
• exposome
• genomics
• nanomaterials
• neuroendocrinology
• proteomics
• xenobiotics

• LPS
• Macrophage polarization
• Signal transduction
• TNF-α
• mRNA stability

• TNF
• cell death
• lymphotoxin

• Flow cytometry
• Glucocorticoids
• Interleukin-1beta
• Monocyte subsets
• Neuromyelitis optica
• Tumor necrosis factor-alpha

• Animals
• Cerebrospinal Fluid
• Cochlea/pathology
• Evoked Potentials, Auditory, Brain Stem
• Gerbillinae
• Humans
• Immunohistochemistry
• Interleukin-1/cerebrospinal fluid
• Meningitis, Bacterial/complications
• Ossification, Heterotopic/therapy
• Pneumococcal Infections/complications
• Therapeutic Irrigation

• R01-DC04328 NIDCD NIH HHS

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Evoked Potentials, Auditory, Brain Stem
• Fibrosis/etiology
• Fibrosis/prevention & control
• Free Radical Scavengers/administration & dosage
• Gerbillinae
• Hearing Loss, Sensorineural/etiology
• Hearing Loss, Sensorineural/physiopathology
• Hearing Loss, Sensorineural/prevention & control
• Inflammation/etiology
• Inflammation/prevention & control
• Injections, Intramuscular
• Injections, Spinal
• Labyrinth Diseases/drug therapy
• Labyrinth Diseases/etiology
• Labyrinth Diseases/pathology
• Labyrinth Diseases/prevention & control
• Male
• Meningitis, Bacterial/drug therapy
• Meningitis, Bacterial/microbiology
• Models, Animal
• Ossification, Heterotopic/etiology
• Ossification, Heterotopic/prevention & control
• Reactive Oxygen Species/adverse effects
• Streptococcal Infections/complications
• Streptococcal Infections/drug therapy
• Superoxide Dismutase/administration & dosage

• Giant cell lesion
• Inralesional injections
• Jaw lesions
• Sclerosing agent

• Diphosphonates
• Humans
• Jaw
• Jaw Diseases/surgery
• Jaw Diseases/therapy
• Mouth Mucosa
• Odontogenic Cysts
• Odontogenic Tumors

• FASD
• cytokines
• development
• neuroimmune
• pro-inflammatory

• Adults
• Guideline
• Meningitis
• Meningococcal sepsis

• Fas-receptor
• apoptosis
• cFLIP
• caspase 8
• liver failure

• Daphne oleoides
• Phytochemistry
• chemical constituents
• medicinal properties

• Animals
• Apoptosis
• Aspergillus fumigatus/immunology
• Blotting, Western
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Chemokine CXCL1/genetics
• Chemokine CXCL1/metabolism
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Immunity, Innate/immunology
• Immunoenzyme Techniques
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/microbiology
• Lung/immunology
• Lung/metabolism
• Lung/microbiology
• Macrophages/immunology
• Macrophages/metabolism
• Macrophages/microbiology
• Mice
• Myeloid Cells/immunology
• Myeloid Cells/metabolism
• Myeloid Cells/microbiology
• Neutrophils/immunology
• Neutrophils/metabolism
• Neutrophils/microbiology
• Pulmonary Aspergillosis/immunology
• Pulmonary Aspergillosis/metabolism
• Pulmonary Aspergillosis/microbiology
• Pulmonary Aspergillosis/prevention & control
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction

• P30 RR032136 NCRR NIH HHS
• 5P30GM103415-03 NIGMS NIH HHS
• T32 DK007301 NIDDK NIH HHS
• P30 CA023108 NCI NIH HHS
• 5 P30 CA023108 NCI NIH HHS
• P20-GM103500 NIGMS NIH HHS
• P20 GM103500 NIGMS NIH HHS
• R01AI093808 NIAID NIH HHS
• 2T32DK007301-31A2 NIDDK NIH HHS
• P20 RR020185 NCRR NIH HHS
• R37 AI093808 NIAID NIH HHS
• P30 GM106394 NIGMS NIH HHS
• R01 AI081838 NIAID NIH HHS
• R01AI81838 NIAID NIH HHS
• AIR21105617 PHS HHS
• 5P30RR032136-02 NCRR NIH HHS
• P30 GM103415 NIGMS NIH HHS
• RR020185 NCRR NIH HHS
• 1P30GM106394-01 NIGMS NIH HHS
• 8 P30 GM103415-02 NIGMS NIH HHS
• R01 AI093808 NIAID NIH HHS
• R21 AI105617 NIAID NIH HHS

•

The inflammatory response increases the expression of RAC3 in vitro and in vivo.

RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB) that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF), one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

• Dex, dexamethasone
• GC, glucocorticoids
• GR, glucocorticoid receptor
• Glucocorticoids
• HEK293, human embryonic kidney cells
• LPS, lipopolysaccharide
• NF-κB
• NF-κB, nuclear factor kappa B
• RAC3
• TNF
• TNF, tumor necrosis factor

• Edwardsiella tarda
• LITAF
• Oplegnathus fasciatus
• Red seabream iridovirus
• Streptococcus iniae

• Amino Acid Sequence
• Animals
• Base Sequence
• DNA, Complementary/genetics
• DNA, Complementary/metabolism
• Edwardsiella tarda/physiology
• Fish Proteins/chemistry
• Fish Proteins/genetics
• Fish Proteins/metabolism
• Gene Expression Regulation/drug effects
• Immunity, Innate/drug effects
• Iridoviridae/physiology
• Lipopolysaccharides/pharmacology
• Molecular Sequence Data
• Perciformes/classification
• Perciformes/genetics
• Perciformes/immunology
• Phylogeny
• RNA/genetics
• RNA/metabolism
• Sequence Alignment/veterinary
• Streptococcus/physiology

The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, induced the release of TNF-α and IL-1 from monolayers of peritoneal resident macrophages. The activity of L-RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(−) and poly A(+) fractions obtained from L-RNA applied to oligo(dT)–cellulose chromatography induced TNF-α and IL-1 release. The L-RNA-induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin-D. The LPS-stimulated macrophages, when pre-incubated with [5-³H]-uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL-1β but not with TNF-α, IL-6 or IL-8. The substance secreted (³H-RNA) sediments in the 4–5S region of a 5–20% sucrose gradient. These results show that L-RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population.

In this study levels of prostaglandin E₂ (PGE₂), tumour necrosis factor (TNF) and interleukin-1 (IL-1) alpha in medium from monocyte derived macrophages (MdM) infected with Chlamydia trachomatis (L₂/434/Bu or K biovars). TNF and PGE₂ were found in both cases while IL-1 alpha was not detected. Both TNF and PGE₂ levels were higher in the medium of the MdM infected with K biovars. TNF reached maximum levels 24 h postinfection, and then declined, while PGE₂ levels increased continuously during the infection time up to 96 h post-infection. Addition of dexamethasone inhibited production of TNF and PGE₂. Inhibition of PGE₂ production by indomethacin resulted in increased production of TNF, while addition of PGE₂ caused partial inhibition of TNF production from infected MdM.

Glucocorticoids are potent inhibitors of inflammation and endotoxic shock. This probably occurs through an inhibition of the synthesis of pro-inflammatory cytokines as well as of many of their toxic activities. Therefore, endogenous glucocorticoids (GC) might represent a major mechanism in the control of cytokine mediated pathologies. GC inhibit the synthesis of cytokines in various experimental models. Adrenalectomy or GC antagonists potentiate TNF, IL-1 and IL-6 production in LPS treated mice. GC inhibit the formation of arachidonic acid metabolites and the induction of NO synthase. They also inhibit various activities of cytokines including toxicity, haemodynamic shock and fever. Adrenalectomy sensitizes to the toxic effects of LPS, TNF and IL-1. On the other hand, GC potentiate the synthesis of several cytokine induced APP by the liver. Since many of these proteins have anti-toxic activities (antioxidant, antiprotease etc.) or bind cytokines, this might well represent a GC mediated protective feedback mechanism involving the liver. Not only do GC inhibit cytokines, but in vivo LPS and various cytokines (TNF, IL-1, IL-6) increase blood GC levels through a central mechanism involving the activation of the HPA. Thus, this neuroendocrine response to cytokines constitutes an important immunoregulatory feedback involving the brain.

• Animals
• Cell Line
• Cytokines/metabolism
• Flavanones/chemistry
• Flavanones/pharmacology
• Interleukin-1beta/metabolism
• Interleukin-6/metabolism
• Lipopolysaccharides/pharmacology
• Macrophages/drug effects
• Macrophages/metabolism
• Mice
• Tumor Necrosis Factor-alpha/metabolism

Radiofrequency ablation (RFA) is a thermal energy delivery system used for coagulative cellular destruction of small tumors through percutaneous or intraoperative application of its needle electrode to the target area, and for assisting partial resection of liver and kidney. We tried to evaluate the regional oxidative and pre-inflammatory stress of RFA-assisted wedge lung resection, by measuring the MDA and tumor Necrosis Factor Alpha (TNF-α) concentration in the resected lung tissue of a swine model.

Fourteen white male swines, divided in two groups, the RFA-group and the control group (C-group) underwent a small left thoracotomy and wedge lung resection of the lingula. The wedge resection in the RFA-group was performed using the RFA technique whereas in C-group the simple "cut and sew" method was performed. We measured the malondialdehyde (MDA) and TNF-α concentration in the resected lung tissue of both groups.

In C-group the MDA mean deviation rate was 113 ± 42.6 whereas in RFA-group the MDA mean deviation rate was significantly higher 353 ± 184 (p = 0.006). A statistically significant increase in TNF-α levels was also observed in the RFA-group (5.25 ± 1.36) compared to C-group (mean ± SD = 8.48 ± 2.82) (p = 0.006).

Our data indicate that RFA-assisted wedge lung resection in a swine model increases regional MDA and TNF-a factors affecting by this oxidative and pre-inflammatory stress of the procedure. Although RFA-assisted liver resection can be well tolerated in humans, the possible use of this method to the lung has to be further investigated in terms of regional and systemic reactions and the feasibility of performing larger lung resections.