REDUCTIONS IN THE ACTIVATION OF ERK AND JNK ARE ASSOCIATED WITH DECREASED IL-2 PRODUCTION IN T-CELLS FROM ELDERLY HUMANS STIMULATED BY THE TCR CD3 COMPLEX AND COSTIMULATORY SIGNALS/

T cells from elderly humans often display impaired IL-2 production, bu t the mechanisms are unknown. Because the activities of extracellular signal-regulated kinases (ERK) and c-Jun NH2-terminal kinases (JNK) ar e important for IL-2 production, the current study evaluated if aberra ncies in the expression and activation of ERK2 or JNK might underlie d ecreased IL-2 production by human T cells during aging. The present re sults show that diminished ERK2 and JNK catalytic activities were comm only detected in T cells from elderly humans stimulated with anti-CDS mAb OKT3 plus PMA. These reductions did not represent temporal shifts in activation or altered expression of ERK2 or JNK. In addition, the r eductions of ERK2 activation in stimulated T cells from elderly indivi duals were accompanied by decreased Raf-l kinase activation and could be observed without coexisting impairments in JNK activation, Stimulat ion of ERK2 activation in elderly T cells correlated with IL-2 product ion and decreased ERK2 activation was consistently associated with red uced IL-2 production. Although the age-related decreases in JNK activa tion were accompanied by reduced IL-2 production, substantial impairme nts of JNK activation were observed with diminished ERK2 activation, M oreover, anti-CD3/PMA-stimulated T cells from elderly individuals that displayed normal JNK activation and impaired ERK2 activation continue d to demonstrate reduced IL-2 production. These findings show that imp airments in the activation of ERK2 and JNK can accompany decreased IL- 2 production by T cells from elderly humans and further suggest that a berrancies in TCR/CD3-dependent activation of the Raf-1/MEK/ERK2 casca de may be rate-limiting for the full induction of IL-2. (C) 1997 Acade mic Press.