AGE-RELATED DECREASES IN IL-2 PRODUCTION BY HUMAN T-CELLS ARE ASSOCIATED WITH IMPAIRED ACTIVATION OF NUCLEAR TRANSCRIPTIONAL FACTORS AP-1 AND NF-AT

Although transcriptional factors AP-1 and nuclear factor of activated T cells (NF-AT) are important for the normal induction of IL-2, it is unknown if the age-related decline in IL-2 production by activated hum an T cells may be associated with aberrancies in transcriptional regul atory proteins, In the current studies, IL-2 production by T cells fro m elderly (mean 78 years) and young (mean 37 years) humans was measure d in cultures stimulated with PHA, PHA plus PMA, crosslinked anti-CDS mAb OKT3 plus PMA, or PMA plus ionomycin. Substantial decreases of IL- 2 production were observed for cell cultures from 7 of 12 elderly indi viduals in response to the different stimuli, whereas the levels of IL -2 produced by stimulated T cells from other elderly individuals were equivalent to those observed for stimulated T cells of young subjects. Analyses of nuclear extracts by electrophoretic DNA mobility shift as says showed that decreased IL-2 production by stimulated T cells of el derly individuals was closely associated with impairments in the activ ation of both AP-1 and NF-AT. By contrast, T cells from elderly subjec ts with normal levels of IL-2 production exhibited normal activation o f AP-1 and NF-AT, In addition, the results of competition experiments analyzing the normal components of NF-AT showed that the age-related r eductions in stimulus-dependent NF-AT complexes corresponded to the sl ow migrating complexes that were composed of c-Fos/c-Jun AP-1. The res ting and stimulated levels of NF kappa B were reduced in T cells from certain elderly individuals; however, alterations of NF kappa B did no t correlate with changes in IL-2 expression. Thus, these results show that age-related impairments in the activation of AP-1 and NF-AT are c losely associated with decreased expression of IL-2 and further sugges t that aberrancies in the signaling pathways important for the inducti on of transcriptionally active c-Fos/c-Jun AP-1 may contribute to the impaired activation of NF-AT. (C) 1996 Academic Press, Inc.