THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE IS ACTIVATED BY LIGATION OF THE T-LYMPHOCYTE OR B-LYMPHOCYTE ANTIGEN RECEPTORS, FAS OR CD40, BUT SUPPRESSION OF KINASE-ACTIVITY DOES NOT INHIBIT APOPTOSIS INDUCED BY ANTIGEN RECEPTORS

We have investigated the activation of the p38 mitogen-activated prote in kinase (MAPK) in normal mouse T and B cells and its role in apoptos is. Cross-linking of the CD3 chains of the TCR complex on proliferatin g T cells resulted in activation of p38 MAPK and MAPKAP kinase-2. Cros s-linking of CD28 failed to activate p38 MAPK or MAPKAP kinase-2, but synergized strongly with low doses of anti-CD3. Cross-linking of Fas o n T cells also induced rapid activation of p38 MAPK and MAPKAP kinase- 2. The in vivo activation of MAPKAP kinase-2 in response to cross-link ing of CD3, Fas, or CD3 and CD28 was shown to be dependent on p38 MAPK activity using a specific inhibitor, SB 203580, SB 203580 did not inh ibit activation-induced cell death in T cells when used at concentrati ons that suppressed activation of MAPKAP kinase-2 in vivo. Cross-linki ng of the B cell Ag receptor (BCR) or CD40 on freshly isolated or LPS- activated splenic B cells or the immature B lymphoma, WEHI 231, result ed in activation of p38 MAPK and MAPKAP kinase-2. In vivo inhibition o f p38 MAPK activity in WEHI 231 cells by SB 203580 had no effect on ei ther BCR-induced apoptosis or anti-CD40-mediated suppression of apopto sis. We conclude that the activation of p38 MAPK and MAPKAP kinase-2 b y cross-linking of the TCR, BCR, Fas, or CD40 was not correlated with their roles in regulating lymphocyte survival, and that suppression of kinase activity did not inhibit the induction of apoptosis.