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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Identification and Characterization of a Novel Class of Interleukin-1 Post-Translational Processing Inhibitors

David G. Perregaux, Patricia McNiff, Ronald Laliberte, Natalie Hawryluk, Heather Peurano, Ethan Stam, Jim Eggler, Richard Griffiths, Mark A. Dombroski and Christopher A. Gabel
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 187-197;
David G. Perregaux
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Patricia McNiff
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Ronald Laliberte
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Natalie Hawryluk
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Heather Peurano
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Ethan Stam
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Jim Eggler
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Richard Griffiths
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Mark A. Dombroski
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Christopher A. Gabel
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Abstract

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.

Footnotes

  • Abbreviations:
    IL
    interleukin
    LPS
    lipopolysaccharide
    CRID
    cytokine release inhibitory drug
    FBS
    fetal bovine serum
    ELISA
    enzyme-linked immunosorbent assay
    PMSF
    phenylmethylsulfonyl fluoride
    CTL
    cytotoxic T lymphocyte
    SFM
    serum-free medium
    PAGE
    polyacrylamide gel electrophoresis
    PBS
    phosphate-buffered saline
    TCA
    trichloroacetic acid
    LDH
    lactate dehydrogenase
    SAA
    serum amyloid A
    • Received April 4, 2001.
    • Accepted June 26, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Identification and Characterization of a Novel Class of Interleukin-1 Post-Translational Processing Inhibitors

David G. Perregaux, Patricia McNiff, Ronald Laliberte, Natalie Hawryluk, Heather Peurano, Ethan Stam, Jim Eggler, Richard Griffiths, Mark A. Dombroski and Christopher A. Gabel
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 187-197;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Identification and Characterization of a Novel Class of Interleukin-1 Post-Translational Processing Inhibitors

David G. Perregaux, Patricia McNiff, Ronald Laliberte, Natalie Hawryluk, Heather Peurano, Ethan Stam, Jim Eggler, Richard Griffiths, Mark A. Dombroski and Christopher A. Gabel
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 187-197;
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