HYDROCORTISONE AND HUMAN-LYMPHOCYTES - INCREASES IN CYCLIC ADENOSINE 3'-5'-MONOPHOSPHATE AND POTENTIATION OF ADENYLATE CYCLASE-ACTIVATING AGENTS

Abstract

The effect of hydrocortisone on the cAMP response of human lymphocytes and polymorphonuclear leukocytes was studied. Hydrocortisone (10-6-10-3 M) caused a dose-dependent increase in the cAMP content of human lymphocytes which occurred rapidly (within 1 min); the cAMP level peaked at .apprx. 10 min, remained elevated for 90 min and decreased promptly to base line if the cells were washed free of hydrocortisone. In contrast to its effects on lymphocytes, hydrocortisone caused only a small dose-dependent increase in cAMP content of polymorphonuclear leukocytes which became significant only at high concentrations. Hydrocortisone (10-6-10-3 M) markedly potentiated the effect of many adenylate cyclase-stimulating agents including .beta.-adrenergic stimuli, histamine, adenosine, prostaglandin [PG] E1 and cholera enterotoxin. The biochemical mechanism(s) of these actions of hydrocortisone were explored. Hydrocortisone did not exert its effects by blocking extracellular cAMP efflux, by inducing protein synthesis, by activating PG metabolic pathways or by preventing receptor (e.g., .beta.-adrenergic receptor) desensitization. Hydrocortisone probably does not work as a cAMP phosphodiesterase inhibitor, as it did not inhibit lymphocyte phosphodiesterase and the magnitude of synergistic potentiation by hydrocortisone was greater than that of potent phosphodiesterase inhibitors. Hydrocortisone might act on the adenylate cyclase enzyme system by other, unknown mechanism(s). The ability of hydrocortisone to increase cAMP and especially to potentiate adenylate cyclase-stimulating agonists may partly explain the potent in vivo antiinflammatory effect of corticosteroids in man.