Anti-immunoglobulin (anti-Ig, anti-mu is commonly used) activates resting mouse B-cells to proliferate but not to differentiate and secrete Ig. Differentiation requires additional help from T-cells including soluble factors such as lymphokines. The capability of lymphokines, alone and in combination, to promote the differentiation of anti-mu activated B-cells has been investigated. Some lymphokines, like interleukin (IL) 2 and 3, as well as human-interferon beta-2 (IL-6), have no significant effect on differentiation. IL-4 and 5 maintain cell growth but do not lead to differentiation, which requires multiple factors present in ConA supernatant or partially purified TRF. Anti-mu and interferon-gamma (IFN-gamma) exert both positive and negative effects on B-cell maturation. Anti-mu induces cell proliferation. IFN-gamma enhances Ig transcription, but it has no apparent proliferation or differentiation activity. Anti-mu and IFN-gamma inhibit Ig secretion by causing the accumulation of nuclear mu-RNA precursors. Although phorbol ester plus ionomycin induce cell proliferation, the negative effect of anti-mu in RNA processing could not be mimicked by these reagents. I show that anti-mu and IFN-gamma interfere with the splicing of nuclear hnRNA. This phenomenon is independent of known 2'-5'(A)n synthetase activity. The data suggest that post-transcriptional regulation of mu-RNA processing might be a critical event in controlling the generation of the plasma cells (which secrete IgM), memory precursor cells or abortive cells (both of which do not secrete IgM).