REDUCTION IN SUPEROXIDE ANION SECRETION AND BACTERICIDAL ACTIVITY OF NEUTROPHILS FROM AGED RATS - REVERSAL BY THE COMBINATION OF GAMMA-INTERFERON AND GROWTH-HORMONE

Polymorphonuclear neutrophils (PMN) from bone marrow of 24-month-old r ats kill Escherichia coil less efficiently than PMN from 3-month-old r ats. Secretion of O-2(-) and killing off. cell by PMN from both young and old rats can be significantly augmented by preincubation with eith er 250 U of gamma interferon (IFN-gamma) or 250 ng of growth hormone ( GH) per ml. This priming is specific, because neutralizing monoclonal antibodies against either IFN-gamma or GH completely abrogate the enha nced O-2(-) secretion by PMN from young rats. However, in contrast to PMN from young rats, PMN from aged rats are not primed to kill E. coli by 10-fold-lower concentrations of either IFN-gamma (25 U/ml) or GH ( 25 ng/ml). To explore the mechanism for the reduction in bacterial kil ling by PMN from old rats, a syngeneic GH-secreting pituitary cell lin e (GH(3)) was implanted in vivo. PMN from GH(3)-treated aged rats, but not control aged rats, could now be primed in vitro for O-2(-) secret ion by IFN-gamma (25 U/ml). Although PMN from aged rats do not respond to the lower doses of either IFN-gamma or GB, the combination of both reagents totally restores the ability of PMN to secrete O-2(-) and to kill E. coil. This synergistic priming is observed with PMN from aged rats, but not with those from young rats, and can be detected when bo th reagents are added simultaneously or when they are added in either sequence. Furthermore, addition of a monoclonal antibody against eithe r IFN-gamma or GH abrogates the synergism of these two molecules. Coll ectively, these data identify an important alteration in myeloid cells from aged rodents by showing that their PMN are intrinsically unable to respond to low concentrations of IFN-gamma by secreting O,and killi ng bacteria. The results also define a previously unrecognized synergi sm in PMN from aged animals by showing that GH synergizes with IFN-gam ma both in vivo and in vitro to restore these suppressed responses.