MRL/MP-lpr/lpr (MRL/l) mice spontaneously develop an age-related autoimmune disease concomitant with interleukin-2 (IL-2) defects. Induction of IL-2 receptor (IL-2R), IL-2 production and subsequent de novo DNA synthesis in MRL/l mice by the tumour-promoting phorbol ester 12-o-tetradecanoyl phorbol 13-acetate (TPA) and calcium ionophore (A23187) were examined. These two compounds given together induced significant IL-2R expression, IL-2 production, and de novo DNA synthesis of spleen cells from this murine strain, as did concanavalin A (Con A) plus TPA. TPA and A23187 may bypass the early steps of activation by mitogens in murine lymphocytes. However, even though these IL-2 defects could be overcome to some extent, the response of MRL/l mice to these stimuli was considerably lower than the enhanced IL-2R expression and IL-2 production of MRL/MP-+/+(MRL/n) control mice. These results suggested that the failure to respond to mitogens in these mice may be due, at least in part, to failure of receptor signal transduction, and to defects of molecular and biochemical reactions following signal transduction.