Regulation of Ig-induced eosinophil degranulation by adenosine 3',5'-cyclic monophosphate.
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 beta-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.
Kita
H
H
Department of Immunology, Mayo Graduate School of Medicine, Rochester, MN 55905.
Abu-Ghazaleh
R I
RI
Gleich
G J
GJ
Abraham
R T
RT
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects* / Q000276:immunology; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology
D007074:Immunoglobulin G; D015124:8-Bromo Cyclic Adenosine Monophosphate; C050086:N(6)-benzoyl-cyclic AMP; D003994:Bucladesine; D002772:Cholera Toxin; D013806:Theophylline; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol; D000420:Albuterol; D015056:1-Methyl-3-isobutylxanthine