Relatively little is known about changes in soluble receptors and otheragonists/antagonists that may regulate cytokine actions in aging humans. Wehave studied age-associated changes in human subjects of (a) the plasmalevels of interleukin-1 soluble receptor (IL-1sRII), interleukin-1 receptorantagonist (IL-1ra), tumor necrosis factor soluble receptor-II(75kDa;TNFsRII), and interleukin-6 soluble receptor (IL-6sR) and (b) the abilityof their blood mononuclear cells to produce those soluble factorsspontaneously and after phytohemagglutinin (PHA) stimulation. Agingsubjects (50-67 years) had significantly higher plasma levels of IL-1ra,significantly lower levels of TNFsRII and IL-6sR than young subjects (25-35years), and no significant change in the level of IL-1sRIL There was lessspontaneous output of IL-1ra and TNFsRII by peripheral blood mononuclearcells (PBMC) of aging than of young subjects, but equivalent output of bothfactors in response to PHA stimulation. Thus, the basal (homeostatic)output of those two factors declined with age, but the potential of thePBMC to produce the factors on stimulation did not. PHA stimulation of PBMCof either age group significantly inhibited the output of IL-6sR. Thesedifferences between the young adult and aging subjects, along with reportedchanges in the corresponding cytokines, presumably foreshadow changes thatbecome more marked with further aging Therefore, immunological processesthat depend on, or are modulated by, proinflammatory cytokines may differbetween young and aged subjects as a consequence of the availability ofregulatory soluble receptors and related agonists or antagonists. Theresults of this study highlight the need for further studies of the rolesplayed by soluble receptors, and similar agonists/antagonists, in theimmune responses of aged adults.