Nerve Growth Factor Inhibits Apoptosis in Memory B Lymphocytes via Inactivation of p38 MAPK, Prevention of Bcl-2 Phosphorylation, and Cytochrome c Release

Abstract

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. In factorstarved memory B cells, the addition of exogenous NGF promptly induced p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK), dephosphorylation. Conversely, withdrawal of endogenous NGF was followed by p38 MAPK activation and translocation onto mitochondria, whereby it combined with and phosphorylated 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 from Bcl-2-negative MDCK cells loaded with recombinant Bcl-2. Apoptosis induced by NGF neutralization could be blocked by the specific p38 MAPK inhibitor SB203580 or by Bcl-2 mutations in Ser-87 or Thr-56. These data demonstrate that the molecular mechanisms underlying the survival factor function of NGF critically rely upon the continuous inactivation of p38 MAPK, a Bcl-2-modifying enzyme.

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade

“…On the other hand, p38 can phosphorylate Bcl-2 on Ser 87 and Thr 56 during growth factor deprivation. p38-mediated phosphorylation of Bcl-2 caused mitochondrial leakage of cytochrome c and was therefore proapoptotic [46]. Bcl-2 is thus a good candidate for mediating the effect of p38 at the mitochondria.…”

Nerve Growth Factor-dependent Survival of CESS B Cell Line Is Mediated by Increased Expression and Decreased Degradation of MAPK Phosphatase 1

“…Forced expression of active MKP-1 is able to prevent the effect of NGF neutralization upon apoptosis. SAPK, induced by appropriate stimuli, was described in memory B lymphocytes and human U937 monocytic cell line, respectively (4,39). In this compartment, the activated enzymes bind and phosphorylate Bcl-2 or Bcl-X L protein, an event that triggers the apoptotic process.…”

“…Conversely, when NGF is added to factor-starved cells, p38 MAPK is promptly deactivated and, hence, Bcl-2 phosphorylation is inhibited (4). In this paper, we characterize the NGFinduced phosphatase MKP-1, which is responsible for active p38 MAPK dephosphorylation in CESS cell line and which plays a relevant role in NGF-mediated autocrine circuit of survival.…”

“…The final result of JNK and p38 MAPK mitochondrial localization is the release of cytochrome c and SMAC/DIABLO (4,39,56). By contrast, ERK localization on mitochondria was instead reported as related to Bad phosphorylation through interaction with PKC⑀, resulting in a mitochondrial activity likely to be an inhibition of cell apoptosis (52).…”

Anti-nerve growth factor Ab abrogates macrophage-mediated HIV-1 infection and depletion of CD4+T lymphocytes in hu-SCID mice

“…The in vitro deprivation of NGF by an anti-NGF Ab leads to a selective apoptosis-mediated death of HIV macrophages, thus confirming the essential role of this autocrine factor in HIV macrophage survival (17). Studies conducted in another model of bone marrow-derived cells (memory B lymphocytes) have demonstrated that the expression of p75 receptor in conditions of NGF deprivation activates a series of events based on p38 mitogen-activated protein kinase activation and translocation onto the mitochondria, whereby it combines with phosphorylated Bcl-2, triggering the apoptotic cascade (39). A similar mechanism may play a role in HIV-infected macrophages, although its demonstration is still required.…”