Retinoic acid (RA) increases antibody production in vivo but its role in B-cell activation is unclear. In a model of purified mouse splenic B cells stimulated by CD40 coreceptor (as a surrogate of T cell co-stimulation), IL-4, a principal Th-2 cytokine, and ligation of the B-cell antigen receptor, CD40 engagement or IL-4 alone induced B-cell activation indicated by increased Ig gamma l germline transcripts,cell proliferation, and surface (s)IgGl expression, while triple stimulation with the combination of anti-CD40/IL-4/anti-mu synergized to heighten B-cell activation. Although RA was growth inhibitory for anti-CD40-activated B cells, RA increased the proportion of B cells that had more differentiated phenotypes, such as expression of higher level of activation-induced deaminase, Blimp-1, CD138/syndecan-1 and sIgG1. Overall, RA can promote B-cell maturation at the population level by increasing the number of sIgG1 and CD 138 expressing cells, which may be related to the potentiation of Immoral immunity in vivo. (c) 2007 Elsevier Inc. All rights reserved.