TY - JOUR T1 - Identification and Characterization of a Novel Class of Interleukin-1 Post-Translational Processing Inhibitors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 187 LP - 197 VL - 299 IS - 1 AU - David G. Perregaux AU - Patricia McNiff AU - Ronald Laliberte AU - Natalie Hawryluk AU - Heather Peurano AU - Ethan Stam AU - Jim Eggler AU - Richard Griffiths AU - Mark A. Dombroski AU - Christopher A. Gabel Y1 - 2001/10/01 UR - http://jpet.aspetjournals.org/content/299/1/187.abstract N2 - 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 procytokine 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 pharmacological 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 procytokine 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. The American Society for Pharmacology and Experimental Therapeutics ER -