Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors.
Lipopolysaccharide (LPS)-activated monocytes and macrophages produce large quantities of pro-interleukin (IL)-1beta 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-1beta 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-1beta post-translational processing. These agents, both diarylsulfonylureas, block formation of mature IL-1beta 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-alpha (TNFalpha), and IL-1RA, but 30-fold less IL-1beta 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 TNFalpha. These novel agents, therefore, act as selective cytokine release inhibitors and define a new therapeutic approach for controlling IL-1 production in inflammatory diseases.
Perregaux
D G
DG
Department of Antibacterials, Immunology, and Inflammation, Pfizer Global Research and Development, Pfizer, Inc., Groton, Connecticut, USA.
McNiff
P
P
Laliberte
R
R
Hawryluk
N
N
Peurano
H
H
Stam
E
E
Eggler
J
J
Griffiths
R
R
Dombroski
M A
MA
Gabel
C A
CA
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007038:Hypotonic Solutions; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects
D016207:Cytokines; D007038:Hypotonic Solutions; D007375:Interleukin-1; D008070:Lipopolysaccharides; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D008715:Methionine