Nerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome c release

Survival of memory B lymphocytes is tightly linked to the integrity of the Bcl-2 protein and is regulated by a nerve growth factor (NGF) autocrine circuit. Infactor-starved memory B cells, the addition of exogenous NGF promptly induced p38mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK),dephosphorylation. Conversely, withdrawal of endogenous NGF was followed by p38MAPK activation and translocation onto mitochondria, whereby it combined with andphosphorylated Bcl-2, as assessed by co-immunoprecipitation and kinase assays in vivo and in vitro. Mitochondria isolated from human memory B cells, then exposed to recombinant p38 MAPK, released cytochrome c, as did mitochondria fromBcl-2-negative MDCK cells loaded with recombinant Bcl-2. Apoptosis induced by NGFneutralization could be blocked by the specific p38 MAPK inhibitor SB203580 or byBcl-2 mutations in Ser-87 or Thr-56. These data demonstrate that the molecularmechanisms underlying the survival factor function of NGF critically rely uponthe continuous inactivation of p38 MAPK, a Bcl-2-modifying enzyme