Evidence that the functional responses of human neutrophils occur independently of transient elevations in cyclic AMP levels

L. Simchowitz, I. Spilberg, J. P. Atkinson

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25 Scopus citations

Abstract

Exposure of human neutrophils to the tripeptide formyl-methionyl-leucyl-phenylalanine (FMLP) leads to a transient, 2-3 fold elevation of adenosine-3',5'-cyclic monophosphate (cAMP) that peaks at 5-15 seconds. This cAMP transient has been hypothesized as constituting an early activation event that may be responsible for subsequent functional responses. In order to evaluate the dependence of several FMLP-stimulated functional responses on elevated cAMP levels, we utilized 9-(tetrahydro-2-furyl)adenine (SQ 22,536), a putative inhibitor of adenylate cyclase. Pretreatment of cells with SQ 22,536 (1-1000 μM) caused dose-dependent inhibition of the FMLP (0.1 μM)-induced cAMP elevation (ID50 ~ 5 μM). Similar results were observed when cells were activated by the divalent cation ionophore A23187 (20 μM). At 1000 μM, a drug concentration which completely abolished the cAMP transient, SQ 22,536 had no effect on FMLP-stimulated superoxide radical (O2-) generation, granule enzyme release, or chemotaxis and only a modest inhibitory effect on A23187-induced O2- production. These studies strongly suggest that these FMLP- and A23187-induced responses occur independently of a transient elevation of cAMP and that, in intact human neutrophils, SQ 22,536 is a non-toxic inhibitor of adenylate cyclase.

Original languageEnglish
Pages (from-to)35-47
Number of pages13
JournalJournal of Cyclic Nucleotide Research
Volume9
Issue number1
StatePublished - Jan 1 1983

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