Apoptosis signal-regulating kinase (ASK)-1 mediates apoptosis in B cells (34.6)

Abstract

Abstract Engagement of membrane immunoglobulin (mIg) on B cells results in reduction of the mitochondrial membrane potential (ƒ¢ƒμm) and apoptosis, which plays a crucial role in the regulation of immune responses. In this study, we show that the apoptosis signal-regulating kinase 1 (ASK1)-JNK1 signaling pathway participates in mIg-induced apoptosis in normal B cells as well as WEHI-231 B lymphoma cells. Stimulation of WEHI-231 cells with anti-IgM induces phosphorylation and subsequent activation of ASK1, leading to JNK activation. Anti-IgM stimulation produces superoxide anions (O2-), accompanied by loss of ƒ¢ƒμm and an increase in cells with sub-G1 DNA content. Anti-IgM-induced O2- production, loss of ƒ¢ƒμm, and increase in the sub-G1 fraction were all reduced substantially in WEHI-231 cells overexpressing a dominant-negative form of ASK1, compared with control vector alone. The mIg-mediated O2- production, loss of ƒ¢ƒμm, and increase in the sub-G1 fraction were partially abrogated by the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC). Similarly to WEHI-231 B lymphoma cells, the mIg-mediated apoptotic features were moderately compromised in mouse ASK1-deficient B cells. Taken together, these results suggest that mIg engagement induces JNK activation through ASK1 activation, resulting in production of O2- that leads to loss of ƒ¢ƒμm and finally to apoptosis.