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Regulation of macrophage lysosomal secretion by adenosine, adenosine phosphate esters, and related structural
Abstract:
Zymosan particle-stimulated beta-galactosidase secretion by mouse peritoneal macrophages was found to be inhibited by micromolar concentrations of adenosine, AMP, ADP, and ATP. Inhibition by all four agents was increased to approximately 80% by adding erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 10 microM) an adenosine deaminase inhibitor, to the incubation medium. The inhibition of lysosomal enzyme secretion by ATP, ADP, and AMP was reversed by adding alpha, beta -methylene ADP (100 microM), a 5'-nucleotidase inhibitor, to the incubation medium. Inhibition by adenosine, however, was unaffected by alpha, beta -methylene ADP indicating that the inhibition by AMP, ADP, and ATP only occurred after they had been converted to adenosine by cell surface phosphohydrolases, including 5'-nucleotidase. Theophylline, a competitive antagonist of the binding of adenosine to plasma membrane adenosine receptors, failed to reverse the inhibitory effect of adenosine indicating the probable site of adenosine action to be intracellular. Other purine nucleosides, e.g., guanosine, and several purine and ribosemodified structural analogues of adenosine also inhibited zymosan-stimulated beta-galactosidase secretion, while xanthosine and certain pyrimidine nucleosides, e.g., thymidine, were inactive in this respect.
Insights
Adenosine and its related compounds, including AMP, ADP, and ATP, inhibit beta-galactosidase secretion in macrophages. This inhibition primarily occurs intracellularly after conversion to adenosine, impacting immune cell function.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Macrophages play a crucial role in the innate immune system, mediating inflammatory responses.
- Lysosomal enzyme secretion is a key function of macrophages involved in pathogen clearance and tissue remodeling.
- Purinergic signaling, involving adenosine and its nucleotides, is known to modulate immune cell activity.
Purpose of the Study:
- To investigate the effect of adenosine and its related nucleotides on zymosan-stimulated beta-galactosidase secretion by mouse peritoneal macrophages.
- To elucidate the mechanism of inhibition, including the role of cell surface enzymes and adenosine receptors.
Main Methods:
- Primary mouse peritoneal macrophages were stimulated with zymosan particles.
- Beta-galactosidase secretion was measured in the presence of various adenosine analogs, nucleotides, and enzyme inhibitors (erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and alpha, beta -methylene ADP).
- Theophylline was used to assess the involvement of plasma membrane adenosine receptors.
Main Results:
- Adenosine, AMP, ADP, and ATP significantly inhibited zymosan-induced beta-galactosidase secretion.
- Inhibition was potentiated by EHNA, an adenosine deaminase inhibitor, and largely reversed by alpha, beta -methylene ADP, a 5'-nucleotidase inhibitor, indicating conversion to adenosine.
- Theophylline did not reverse adenosine's inhibitory effect, suggesting intracellular action, while other purine nucleosides also showed inhibitory effects.
Conclusions:
- Adenosine and its nucleotides are potent inhibitors of macrophage lysosomal enzyme secretion, acting primarily intracellularly after conversion to adenosine.
- This purinergic regulation highlights a novel mechanism influencing macrophage effector functions.
- Findings suggest therapeutic potential for purinergic modulators in inflammatory conditions.