RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 187
OP 197
VO 299
IS 1
A1 David G. Perregaux
A1 Patricia McNiff
A1 Ronald Laliberte
A1 Natalie Hawryluk
A1 Heather Peurano
A1 Ethan Stam
A1 Jim Eggler
A1 Richard Griffiths
A1 Mark A. Dombroski
A1 Christopher A. Gabel
YR 2001
UL http://jpet.aspetjournals.org/content/299/1/187.abstract
AB 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