We have recently demonstrated that pharmacological agents that elevated cAMP inhibited slgM but not Lyb2 mediated activation of murine B lymphocytes. In this report we show evidence for differential regulation of prostaglandin E2 (PGE2), a physiological agent that elevated cAMP and IFN-gamma on slgM and Lyb2 mediated B cell activation. PGE2 inhibited anti-IgM but not anti-Lyb2 induced DNA synthesis in a dose-dependent manner. Interestingly, rIFN-gamma also inhibited anti-Ig but not anti-Lyb2 induced DNA synthesis. rIFN-gamma exerted its effects directly on B cells since depletion of T cells and G-10 Sephadex adherent cells did not alter effects of IFN-gamma on anti-IgM and anti-Lyb2 induced DNA synthesis. Pretreatment of B cells with IL-4 and/or IL-5 did not prevent the IFN-gamma mediated inhibition of the anti-IgM response. The inhibitory effect of IFN-gamma was observed during early stages of B cell activation. Thus IFN-gamma inhibited anti-mu induced blast transformation and subsequent progression into the G1 phase of the cell cycle. The differential effects exerted by PGE2 and rIFN-gamma appeared to be mediated by distinct mechanisms. Thus PGE2 but not rIFN-gamma, at concentrations inhibitory to the slgM response, induced elevation of intracellular cAMP levels. These results demonstrate that physiologically relevant immunomodulators such as PGE2 and IFN-gamma can differentially regulate murine B cell responses mediated through the antigen receptor and Lyb2 molecules by cAMP dependent and independent mechanisms. Relevance of this regulation for the induction of antibody synthesis by Th1 and Th2 types of helper T cells is discussed.