Regulation of Ig-induced eosinophil degranulation by adenosine 3',5'- cyclic monophosphate

• Published in: The Journal of immunology (1950) Vol. 146; no. 8; pp. 2712 - 2718
• Main Authors: Kita, H, Abu-Ghazaleh, RI, Gleich, GJ, Abraham, RT
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.04.1991
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Albuterol - pharmacology; Bucladesine - pharmacology; Cell Degranulation - drug effects; Cell Degranulation - immunology; Cholera Toxin - pharmacology; Cyclic AMP - analogs & derivatives; Cyclic AMP - pharmacology; Dinoprostone - pharmacology; Eosinophils - physiology; Humans; Immunoglobulin G - physiology; In Vitro Techniques; Isoproterenol - pharmacology; Signal Transduction - drug effects; Theophylline - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.146.8.2712

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.