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Originally published In Press as doi:10.1074/jbc.M211596200 on March 6, 2003

J. Biol. Chem., Vol. 278, Issue 19, 16567-16578, May 9, 2003
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Glutathione S-Transferase Omega 1-1 Is a Target of Cytokine Release Inhibitory Drugs and May Be Responsible for Their Effect on Interleukin-1beta Posttranslational Processing*

Ronald E. Laliberte, David G. Perregaux, Lise R. Hoth, Philip J. Rosner, Crystal K. Jordan, Kevin M. Peese, James. F. Eggler, Mark A. Dombroski, Kieran F. Geoghegan, and Christopher A. GabelDagger

From the Departments of Antibacterials, Immunology and Inflammation, and Exploratory Medicinal Sciences, Pfizer Global Research and Development, Pfizer, Inc., Groton, Connecticut 06340

Stimulus-induced posttranslational processing of human monocyte interleukin-1beta (IL-1beta ) is accompanied by major changes to the intracellular ionic environment, activation of caspase-1, and cell death. Certain diarylsulfonylureas inhibit this response, and are designated cytokine release inhibitory drugs (CRIDs). CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved. Affinity labeling with [14C]CRIDs and affinity chromatography on immobilized CRID were used in seeking potential protein targets of their action. Following treatment of intact human monocytes with an epoxide-bearing [14C]CRID, glutathione S-transferase (GST) Omega 1-1 was identified as a preferred target. Moreover, labeling of this polypeptide correlated with irreversible inhibition of ATP-induced IL-1beta posttranslational processing. When extracts of human monocytic cells were chromatographed on a CRID affinity column, GST Omega 1-1 bound selectively to the affinity matrix and was eluted by soluble CRID. Recombinant GST Omega 1-1 readily incorporated [14C]CRID epoxides, but labeling was negated by co-incubation with S-substituted glutathiones or by mutagenesis of the catalytic center Cys32 to alanine. Peptide mapping by high performance liquid chromatography-mass spectrometry also demonstrated that Cys32 was the site of modification. Although S-alkylglutathiones did not arrest ATP-induced IL-1beta posttranslational processing or inhibit [14C]CRID incorporation into cell-associated GST Omega 1-1, a glutathione-CRID adduct effectively demonstrated these attributes. Therefore, the ability of CRIDs to arrest stimulus-induced IL-1beta posttranslational processing may be attributable to their interaction with GST Omega 1-1.

* 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.

Dagger To whom correspondence should be addressed: Dept. of Antibacterials, Immunology and Inflammation, Mailstop 8220-2123, PGRD, Pfizer, Inc., Groton, CT 06340. Tel.: 860-441-5483; E-mail: christopher_a_gabel@groton.pfizer.com.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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