We investigated in five normal subjects whether the secretion of GH from lymphocytes would occur spontaneously without mitogens and be regulated by GHRH and somatostatin as in the endocrine system. Peripheral blood mononuclear cells were isolated from heparinized blood by the standard Ficoll-Hypaque gradient centrifugation method, and incubated for up to 7 days with or without GHRH, somatostatin analog (SMS 201-995), cycloheximide, or actinomycin D. GH levels in the lyophilized samples were measured by a highly sensitive enzyme immunoassay. GH concentration in culture medium (5 x 10(5) cells/mL) time dependently increased in all subjects, reaching 0.47 +/- 0.18 ng/L at day 7. A protein synthesis inhibitor (cycloheximide) and RNA synthesis inhibitor (actinomycin D) completely blocked GH secretion from lymphocytes. Immunoreactive GH secreted by unstimulated human lymphocytes was similar to pituitary GH in terms of antigenicity and molecular weight. Physiological concentrations of GHRH (10(-10)-10(-8) mol/L) and SMS 201-995 (10(-8)-10(-6) mol/L) had no effects on the spontaneous secretion of GH from human lymphocytes. These results indicate that GH is spontaneously synthesized de novo and secreted from unstimulated human lymphocytes, and that the regulation of GH in the immune system differs from that in the endocrine system.