The murine pre-B-lymphocyte cell line 70Z /3 may be induced to differentiate to a surface immunoglobulin-positive phenotype by the polyclonal B-cell mitogen, lipopolysaccharide. This is accomplished via activation of an amiloride-sensitive Na+-uptake system ( Rosoff , P. M., and Cantley , L. C. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 7547-7550). Here we show that the active tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) also induces surface IgM expression in 70Z /3 cells. TPA also appears to work by activating a plasma membrane Na+/H+ exchange system. A significant increase in cellular Na+ was detected within 10 min after TPA addition and by 2 h an 80% increase was observed. Amiloride blocked both the induction of surface IgM and the increase in cellular Na+. Further evidence that both TPA and lipopolysaccharide activate Na+/H+ exchange was provided by measurements of intracellular pH with carboxyfluorescein. Both TPA and lipopolysaccharide caused a 0.15 unit increase in cytoplasmic pH within 5 min after addition to the cells at 37 degrees C. The pH change required high extracellular Na+ and was inhibited by amiloride. These data suggest a mechanism by which phorbol esters affect cellular growth and differentiation.