scholarly journals Human macrophages convert l-tryptophan into the neurotoxin quinolinic acid

1992 ◽  
Vol 283 (3) ◽  
pp. 633-635 ◽  
Author(s):  
M P Heyes ◽  
K Saito ◽  
S P Markey
Keyword(s):  
Interferon Gamma ◽  
Quinolinic Acid ◽  
Receptor Agonist ◽  
Chemical Ionization ◽  
Inflammatory Diseases ◽  
Human Peripheral Blood ◽  
Inflammatory Cells ◽  
Ionization Mass ◽  
Dependent Manner ◽  
Aspartate Receptor

Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor agonist quinolinic acid (QUIN) occur in human patients and non-human primates with inflammatory diseases. Such increases were postulated to be secondary to induction of indoleamine 2,3-dioxygenase in inflammatory cells, particularly macrophages, by interferon-gamma. To test this hypothesis, human peripheral-blood macrophages were incubated with L-[13C6]tryptophan in the absence or presence of interferon-gamma. [13C6]QUIN was quantified by gas chromatography and electron-capture negative-chemical-ionization mass spectrometry. [13C6]QUIN was detected in the incubation medium of both unstimulated and stimulated cultures. Exposure to interferon-gamma substantially increased the accumulation of [13C6]QUIN in a dose- and time-dependent manner. The QUIN concentrations achieved exceeded those reported in both cerebrospinal fluid and blood of patients and of non-human primates with inflammatory diseases. Macrophages stimulated with interferon-gamma may be an important source of accelerated L-tryptophan conversion into QUIN in inflammatory diseases.

scholarly journals Human microglia convert l-tryptophan into the neurotoxin quinolinic acid

1996 ◽  
Vol 320 (2) ◽  
pp. 595-597 ◽  
Author(s):  
Melvyn P. HEYES ◽  
Cristian L. ACHIM ◽  
Clayton A. WILEY ◽  
Eugene O. MAJOR ◽  
Kuniaki SAITO ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Quinolinic Acid ◽  
Inflammatory Diseases ◽  
Fetal Brain ◽  
Interferon Γ ◽  
Ionization Mass ◽  
Human Fetal Brain ◽  
Human Microglia ◽  
The Central Nervous System

Immune activation leads to accumulations of the neurotoxin and kynurenine pathway metabolite quinolinic acid within the central nervous system of human patients. Whereas macrophages can convert l-tryptophan to quinolinic acid, it is not known whether human brain microglia can synthesize quinolinic acid. Human microglia, peripheral blood macrophages and cultures of human fetal brain cells (astrocytes and neurons) were incubated with [13C6]l-tryptophan in the absence or presence of interferon γ. [13C6]Quinolinic acid was identified and quantified by gas chromatography and electron-capture negative-chemical ionization mass spectrometry. Both l-kynurenine and [13C6]quinolinic acid were produced by unstimulated cultures of microglia and macrophages. Interferon γ, an inducer of indoleamine 2,3-dioxygenase, increased the accumulation of l-kynurenine by all three cell types (to more than 40 µM). Whereas large quantities of [13C6]quinolinic acid were produced by microglia and macrophages (to 438 and 1410 nM respectively), minute quantities of [13C6]quinolinic acid were produced in human fetal brain cultures (not more than 2 nM). Activated microglia and macrophage infiltrates into the brain might be an important source of accelerated conversion of l-tryptophan into quinolinic acid within the central nervous system in inflammatory diseases.

The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia

2006 ◽  
Vol 290 (5) ◽  
pp. L971-L977 ◽  
Author(s):  
Maiko Moriyama ◽  
Satoru Fukuyama ◽  
Hiromasa Inoue ◽  
Takafumi Matsumoto ◽  
Takahiro Sato ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Diseases ◽  
Human Peripheral Blood ◽  
Collagen Type I ◽  
Eosinophil Infiltration ◽  
Type I ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Eosinophil Cell

Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca2+mobilization and extracellular/signal-regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma.

scholarly journals Hirsutanol A Attenuates Lipopolysaccharide-Mediated Matrix Metalloproteinase 9 Expression and Cytokines Production and Improves Endotoxemia-Induced Acute Sickness Behavior and Acute Lung Injury

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 360 ◽  
Author(s):  
Jan ◽  
Yang ◽  
Wang ◽  
Lin ◽  
Yen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Diseases ◽  
Sickness Behavior ◽  
Inflammatory Cells ◽  
Marine Fungus ◽  
Motor Deficits ◽  
Interstitial Tissue ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Acute Sickness

Activated human monocytes/macrophages, which increase the levels of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, are the essential mechanisms for the progression of sepsis. In the present study, we determined the functions and mechanisms of hirsutanolA (HA), which is isolated from the red alga-derived marine fungus Chondrostereum sp. NTOU4196, on the production of pro-inflammatory mediators produced from lipopolysaccharide (LPS)-treated THP-1 cells. Our results showed that HA suppressed LPS-triggered MMP-9-mediated gelatinolysis and expression of protein and mRNA in a concentration-dependent manner without effects on TIMP-1 activity. Also, HA significantly attenuated the levels of TNF-α, IL-6, and IL-1β from LPS-treated THP-1 cells. Moreover, HA significantly inhibited LPS-mediated STAT3 (Tyr705) phosphorylation, IκBα degradation and ERK1/2 activation in THP-1 cells. In an LPS-induced endotoxemia mouse model, studies indicated that HA pretreatment improved endotoxemia-induced acute sickness behavior, including acute motor deficits and anxiety-like behavior. HA also attenuated LPS-induced phospho-STAT3 and pro-MMP-9 activity in the hippocampus. Notably, HA reduced pathologic lung injury features, including interstitial tissue edema, infiltration of inflammatory cells and alveolar collapse. Likewise, HA suppressed the induction of phospho-STAT3 and pro-MMP-9 in lung tissues. In conclusion, our results provide pharmacological evidence that HA could be a useful agent for treating inflammatory diseases, including sepsis.

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