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J Biol Chem, Vol. 274, Issue 52, 36944-36951, December 24, 1999
From the Department of Respiratory, Allergy, Immunology,
Inflammation, and Infectious Diseases, Pfizer Central Research,
Groton, Connecticut 06340
Mechanisms that regulate conversion of
prointerleukin-1
ATP Treatment of Human Monocytes Promotes Caspase-1 Maturation
and Externalization*
(pro-IL-1) to its mature form by the cysteine
protease caspase-1 are not well understood. In this study, we
demonstrate that mature caspase-1 subunits are produced when human
monocytes are treated with ATP and, like mature IL-1, are released
extracellularly. Characterization of the pharmacological sensitivity of
this stimulus-coupled response revealed that some caspase-1 inhibitors
allow pro-IL-1 secretion, whereas others do not. Two nonselective
alkylating agents, N-ethylmaleimide and phenylarsine oxide,
also blocked maturation and release of pro-IL-1. Two inhibitors of
anion transport, glyburide and ethacrynic acid, blocked maturation of
both caspase-1 and pro-IL-1 and prevented release of the
propolypeptides. Procaspase-3 was detected in monocyte extracts, but
its proteolytic activation was not efficient in the presence of ATP.
Maturation of procaspase-1 and release of the mature enzyme subunits
therefore accompany stimulus-coupled human monocyte IL-1
post-translational processing. Agents that appear to selectively
inhibit mature caspase-1 do not prevent ATP-treated cells from
releasing their cytosolic components. On the other hand, anion
transport inhibitors and alkylating agents arrest ATP-treated monocytes
in a state where membrane latency is maintained. The data provided
support the hypothesis that stimulus-coupled IL-1 post-translational
processing involves a commitment to cell death.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Respiratory,
Allergy, Immunology, Inflammation, and Infectious Diseases, Pfizer
Central Research, Eastern Point Rd., Groton, CT 06340. Tel.:
860-441-5483; Fax: 860-441-5719.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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