THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY IN ACTIVATED AND ANERGIC TH1 CELLS

Stimulation of T cells through the TCR leads to activation of the mito gen-activated protein kinase (MAPK) family members ERK (extracellular signal-regulated kinase) and JNK (jun NH2-terminal kinase). These kina ses act in synergy to increase the activity of the transcription facto r AP-1 which is involved in the transcriptional upregulation of IL-2. Recently a third MAPK member, p38, has been identified. The effects of T cell activation on this pathway have not yet been elucidated. Using two murine Th1 clones, we demonstrate that the p38 pathway is induced upon anti-CD3 plus anti-CD28 crosslinking or PMA plus ionomycin stimu lation. p38 activity was induced fully by anti-CD3 or PMA alone and is not enhanced by costimulation even at low levels of TCR signaling. p3 8 activity peaked at 20 min and was significantly decreased by 2 hr. A nergic (tolerant) Th1 cells showed decreased p38 activity as well as d ecreased ERK and JNK activities even though levels of these proteins r emained unchanged. (C) 1997 Academic Press.