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Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis
- Source :
- FASEB J
- Publication Year :
- 2021
-
Abstract
- Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.
- Subjects :
- Inosine monophosphate
Adenosine monophosphate
Male
Receptor, Adenosine A2A
Purine nucleoside phosphorylase
Adenosine A3 Receptor Antagonists
Pharmacology
Receptor, Adenosine A2B
Biochemistry
Article
chemistry.chemical_compound
Mice
Inosine Monophosphate
Guanosine monophosphate
Genetics
medicine
Animals
Purine metabolism
Inosine
Molecular Biology
Hypoxanthine
Tumor Necrosis Factor-alpha
Receptor, Adenosine A3
Pneumonia, Pneumococcal
Triazoles
Endotoxemia
Adenosine A2 Receptor Antagonists
Interleukin-10
Mice, Inbred C57BL
Disease Models, Animal
Streptococcus pneumoniae
chemistry
Quinazolines
Nucleoside
Biotechnology
medicine.drug
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- FASEB J
- Accession number :
- edsair.doi.dedup.....fd484d5b73cac0c63f9d18b3687afc02