AGE-RELATED REDUCTIONS IN THE ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES P44(MAPK) ERK1 AND P42(MAPK)/ERK2 IN HUMAN T-CELLS STIMULATEDVIA LIGATION OF THE T-CELL RECEPTOR COMPLEX/

Age-related changes in the functional properties of human T cells are well described, but less known about possible changes in T cell signal ling pathways. The signalling pathways mediated by the mitogen-activia ted protein kinases (MAPK) are considered essential for normal cellula r growth and function. Several stimuli trigger MAPK activation in huma n T cells and MEK (MAPK or ERK kinases) are immediate upstream inducer s of MAPK activation. The current study investigated if aging might in fluence the activation and expression of MAPK and MEK in human T cells . Exposure of peripheral blood T cells from young subjects to PHA or c ross-linked anti-CD3 monoclonal antibodies stimulated rapid increases in MAPK and MEK enzymatic activity. By contrast, significant reduction s of MAPK and MEK activation were observed in stimulated T cells from 7 of 13 elderly subjects. Kinetic studies showed that age-related impa irments represented reductions in both the levels and duration of MAPK activation. In addition, Western immunoblot analysis did not reveal s ignificant age-related differences in T cell expression of p42(mapk)/E KR2, p44(mapk)/ERK1, or MEK, suggesting impairments in upstream induce rs of MEK/MAPK activation. Other experiments determined if agents that directly stimulate upstream Ras or Raf kinase components of the early MAPK activation. Treatment of elderly T cells with fluoroaluminate (A lF4-), phorbol esters/Ca2+ ionophores, or okadaic acid stimulated incr eased MAPK activation compared to anti-CD3. However, these agents fail ed to restore MAPK activation in elderly T cells to the levels seen in young T cells. These results suggest that aberrancies in the MAPK act ivation cascade may underline the age-related reductions of MAPK activ ation in human T cells stimulated via the TCR/CD3 complex.