We have investigated the effects of cAMP on Ig-induced human eosinophil activation. Stimulation of human normodense eosinophils with IgG- or secretory IgA (sIgA)-coated Sepharose beads induced cellular degranulation, as measured by the release of the granule protein, eosinophil-derived neurotoxin (EDN). Pretreatment with cAMP analogs (N6,O2,-dibutyryl adenosine-3,':5' cyclic monophosphate; 8-bromoadenosine 3':5' cyclic monophosphate; or N6-benzoyladenosine 3':5' cyclic monophosphate) or cAMP phosphodiesterase-inhibitors (theophylline or isobutylmethyl xanthine (IBMX)) strongly inhibited Ig-induced human eosinophil degranulation. The β-adrenoceptor agonists, isoproterenol and salbutamol, induced relatively low level increases in intracellular cAMP, and weakly suppressed EDN release induced by IgG-coated beads. However, cellular pretreatment with IBMX synergistically enhanced the inhibitory effects of isoproterenol or salbutamol on both IgG and sIgA-induced eosinophil degranulation. Similarly, PGE2 treatment increased intracellular cAMP concentrations in eosinophils and correspondingly inhibited the Ig-dependent cellular degranulation response: co-incubation with IBMX further enhanced both effects of PGE2. Finally, cholera toxin, which irreversibly activates the stimulatory guanine nucleotide-binding protein linked to adenylyl cyclase, strongly inhibited the release of EDN from IgG- or sIgA-stimulated eosinophils. The time-dependent accumulation of cAMP in cholera toxin-treated cells closely paralleled the time courses of inhibition of IgG- and sIgA-induced EDN release after toxin exposure. These data indicate that the cAMP-dependent signal transduction mechanism in eosinophils exerts a negative modulatory effect on the cellular degranulation responses induced by sIgA or IgG. The inhibitory effects of cAMP on eosinophil activation may provide an important physiologic and a clinically relevant therapeutic mechanism for limiting the release of eosinophil-derived cytotoxic proteins during certain allergic or inflammatory responses in vivo.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Immunology|
|State||Published - Jan 1 1991|
ASJC Scopus subject areas
- Immunology and Allergy