Hydrocortisone and human lymphocytes: increases in cyclic adenosine 3':5'-monophosphate and potentiation of adenylate cyclase-activating agents.
We have investigated the effect of hydrocortisone on the cyclic adenosine 3':5'-monophosphate (cAMP) response of human lymphocytes and polymorphonuclear leukocytes. 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 about 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. In addition to increasing lymphocyte cAMP levels, hydrocortisone (10(-6)-10(-3)M) markedly potentiated the effect of many adenylate cyclase-stimulating agents including beta adrenergic stimuli, histamine, adenosine, prostaglandin E1 and cholera enterotoxin. The biochemical mechanism(s) of these actions of hydrocortisone were explored and it was found that hydrocortisone exerted its effects neither by blocking extracellular cAMP efflux, nor by inducing protein synthesis, nor by activating prostaglandin metabolic pathways, nor by preventing receptor (e.g., beta adrenergic receptor) desensitization. Hydrocortisone probably does not work as a cAMP phosphodiesterase inhibitor, since it did not inhibit lymphocyte phosphodiesterase, and the magnitude of synergistic potentiation by hydrocortisone was greater than that of potent phosphodiesterase inhibitors. Thus, 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 anti-inflammatory effect of corticosteroids in man.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis
D011453:Prostaglandins; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D006854:Hydrocortisone