Lipopolysaccharide (LPS)-activated monocytes and macrophages produce large quantities of pro-interleukin (IL)-1β but externalize little mature cytokine.Efficient post-translational processing of the pro-cytokine occurs in vitro when these cells encounter a secretion stimulus such as ATP, cytolytic T cells, or hypotonic stress.Each of these stimuli promotes rapid conversion of 31-kDa pro-IL-1β to its mature 17-kDa species and release of the 17-kDa cytokine.In this study, two novel pharmacol. agents, CP-424,174 and CP-412,245, are identified as potent inhibitors of stimulus-coupled IL-1β post-translational processing.These agents, both diarylsulfonylureas, block formation of mature IL-1β without increasing the amount of pro-cytokine that is released extracellularly, and they inhibit independently of the secretion stimulus used.Conditioned medium derived from LPS-activated/ATP-treated human monocytes maintained in the absence and presence of CP-424,174 contained comparable quantities of IL-6, tumor necrosis factor-α (TNFα), and IL-1RA, but 30-fold less IL-1β was generated in the test agent's presence.As a result of this decrease, monocyte conditioned medium prepared in the presence of CP-424,174 demonstrated a greatly diminished capacity to promote an IL-1-dependent response (induction of serum amyloid A synthesis by Hep3B cells).Oral administration of CP-424,174 to mice resulted in inhibition of IL-1 in the absence of an effect on IL-6 and TNFα.These novel agents, therefore, act as selective cytokine release inhibitors and define a new therapeutic approach for controlling IL-1 production in inflammatory diseases.