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Involvement of eicosanoids in platelet-activating factor-induced modulation of adenylyl cyclase activity in alveolar
F D Beusenberg1, A van Schaik, J G van Amsterdam
1Department of Pharmacology, Faculty of Medicine, Erasmus University, Rotterdam, The Netherlands.
Abstract:
Platelet-activating factor (PAF) induces a dose-dependent biphasic response in adenylyl cyclase activity in antigen-challenged alveolar macrophages (AM), but not in naive AM. Intracellular cyclic AMP levels are enhanced by very low concentrations of PAF (10(-13)-10(-10) M) and decreased by higher PAF concentrations (10(-8)-10(-5) M). The PAF response of adenylyl cyclase could be completely blocked by pretreatment with the PAF receptor antagonist BN 52021. The adenylyl cyclase stimulatory and inhibitory phases are reversed by indometacin (inhibiting cyclo-oxygenase) and AA 861 (inhibiting lipoxygenase). These results show that the PAF-induced response of adenylyl cyclase activity in antigen-challenged AM is achieved by its modulation of intracellular arachidonic acid metabolism.
Insights
Platelet-activating factor (PAF) affects adenylyl cyclase activity in challenged lung cells, with low doses increasing cyclic AMP and high doses decreasing it. This response is mediated by arachidonic acid metabolism.
Area of Science:
- Immunology
- Cellular Biology
- Pharmacology
Background:
- Platelet-activating factor (PAF) is a potent lipid mediator involved in inflammatory responses.
- Alveolar macrophages (AM) play a crucial role in lung immunity and inflammation.
- The precise mechanisms of PAF signaling in AM, particularly concerning adenylyl cyclase activity, require further elucidation.
Purpose of the Study:
- To investigate the effect of Platelet-activating factor (PAF) on adenylyl cyclase activity in antigen-challenged alveolar macrophages (AM).
- To determine the role of intracellular arachidonic acid metabolism in mediating the PAF response in AM.
Main Methods:
- Primary cultures of alveolar macrophages (AM) were challenged with antigen.
- Cells were treated with various concentrations of Platelet-activating factor (PAF).
- Adenylyl cyclase activity and intracellular cyclic AMP levels were measured.
- The effects of PAF receptor antagonist BN 52021, indometacin, and AA 861 were assessed.
Main Results:
- Platelet-activating factor (PAF) induced a dose-dependent biphasic response in adenylyl cyclase activity in antigen-challenged AM, but not in naive AM.
- Low PAF concentrations (10(-13)-10(-10) M) enhanced intracellular cyclic AMP levels, while higher concentrations (10(-8)-10(-5) M) decreased them.
- The PAF-induced adenylyl cyclase response was blocked by the PAF receptor antagonist BN 52021.
- Both stimulatory and inhibitory phases of adenylyl cyclase activity were reversed by indometacin and AA 861, indicating involvement of cyclo-oxygenase and lipoxygenase pathways.
Conclusions:
- The PAF-induced biphasic modulation of adenylyl cyclase activity in antigen-challenged AM is dependent on the PAF receptor.
- Intracellular arachidonic acid metabolism plays a critical role in mediating both the stimulatory and inhibitory effects of PAF on adenylyl cyclase in AM.
- These findings highlight a novel signaling pathway for PAF in lung macrophages involving lipid mediators.