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Cyclic AMP antagonizes mitogen-induced accumulation of inositol phosphates in human peripheral mononuclear leucocytes
L J van Tits1, A Daul, H Grosse-Wilde
1Biochemical Research Laboratories, University of Essen, FRG.
Abstract:
The effect of intracellular increases of cyclic adenosine monophosphate (cAMP) on the accumulation of inositol phosphates (IPs) in response to various mitogens in vitro in human peripheral mononuclear leucocytes (MNL) was investigated. The beta-adrenoceptor agonists inhibited mitogen-induced IPs-accumulation by about 30-50% with a rank order of potency isoprenaline greater than adrenaline much greater than noradrenaline. This rank order corresponded with the order of potency of the beta-adrenoceptor agonists to generate cAMP. The beta-adrenoceptor agonist-induced inhibition of IPs-accumulation in response to mitogen could be completely prevented by the beta 2-adrenoceptor selective antagonist ICI 118,551, but not by the beta 1-adrenoceptor selective antagonist CGP 20712A. Furthermore, the isoprenaline-induced inhibition of IPs-accumulation in response to mitogen could be enhanced by the phosphodiesterase inhibitor IBMX. We conclude that cAMP antagonizes mitogen-induced IPs-accumulation in human peripheral MNL in vitro.
Insights
Cyclic adenosine monophosphate (cAMP) inhibits mitogen-induced inositol phosphate (IP) accumulation in human immune cells. This effect is mediated by beta-adrenoceptors and modulated by phosphodiesterase activity.
Area of Science:
- Immunology
- Cellular Signaling
- Pharmacology
Background:
- Mitogen stimulation of human peripheral mononuclear leucocytes (MNL) leads to inositol phosphate (IP) accumulation.
- Intracellular levels of cyclic adenosine monophosphate (cAMP) can influence cellular responses to various stimuli.
Purpose of the Study:
- To investigate the effect of elevated intracellular cAMP levels on mitogen-induced IP accumulation in human MNL.
- To determine the role of beta-adrenoceptors in mediating this effect.
Main Methods:
- Human peripheral MNL were treated with various mitogens in the presence or absence of beta-adrenoceptor agonists.
- Measurement of inositol phosphate (IP) accumulation.
- Use of selective beta-adrenoceptor antagonists (ICI 118,551 and CGP 20712A) and a phosphodiesterase inhibitor (IBMX).
Main Results:
- Beta-adrenoceptor agonists inhibited mitogen-induced IP accumulation by 30-50% in a potency order of isoprenaline > adrenaline > noradrenaline.
- This inhibition was mediated by beta 2-adrenoceptors, as it was blocked by ICI 118,551 but not CGP 20712A.
- The phosphodiesterase inhibitor IBMX enhanced the inhibitory effect of isoprenaline, suggesting a role for cAMP hydrolysis in regulating this pathway.
Conclusions:
- Elevated intracellular cAMP antagonizes mitogen-induced IP accumulation in human peripheral MNL.
- The beta 2-adrenoceptor is the primary mediator of this inhibitory effect.
- These findings highlight a novel cross-talk mechanism between cAMP signaling and IP-mediated pathways in immune cells.