We have reported previously that in vitro granulomas are inducible by culturing murine spleen cells in the presence of artificial microparticles, dextran beads, and that macrophages and macrophage-derived cytokines (monokines) including interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play a critical role in the initiation of bead-induced granulomas in vitro. To investigate regulatory mechanisms of granuloma formation, we examined the modulatory effects of various mediators such as IL-1, TNF-alpha, interferon-gamma (IFN-gamma), IL-4, IL-6, transforming growth factor-beta (TGF-beta), dexamethasone and prostaglandin E2 (PGE2) on the development of lesions, because these mediators are known to play a pivotal role in inflammatory responses. The lesions were suppressed by the addition of dexamethasone, PGE2 or certain T cell-derived lymphokines such as IL-4 and IFN-gamma. These results suggest that suppressive signals are different from granulomatogenic cytokines including IL-1 and TNF-alpha and that granulomas are regulated by multi-factor dependent mechanisms.