We show that
anti-IgM-induced cell death in a human B
lymphoma cell line, B104, is associated with early intracellular acidification and cell shrinkage. In contrast, another human
B cell lymphoma line, Daudi, less susceptible to
B cell antigen receptor-mediated cell death, responded to
anti-IgM with an early increase in intracellular pH (pH(i)). The
anti-IgM-induced changes of pH(i) were associated with different levels of activation of the
Na(+)/H(+) exchanger isoform 1 (NHE1) as judged by its phosphorylation status. Prevention of
anti-IgM-induced cell death in B104 cells by the
calcineurin phosphatase inhibitor,
cyclosporin A, abrogated both intracellular acidification and cell shrinkage and was associated with an increase in the phosphorylation level of NHE1 within the first 60 min of stimulation. This indicates a key role for
calcineurin in regulating pH(i) and cell viability. The potential role of pH(i) in cell viability was confirmed in Daudi cells treated with an
Na(+)/H(+) exchanger inhibitor
5-(N,N-hexamethylene)amiloride. These observations indicate that the outcome of the
anti-IgM treatment depends on NHE1-controlled pH(i). We suggest that inactivation of the NHE1 in
anti-IgM-stimulated cells results in intracellular acidification and subsequently triggers or amplifies cell death.