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J. Biol. Chem., Vol. 278, Issue 19, 16567-16578, May 9, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/19/16567    most recent M211596200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laliberte, R. E. Articles by Gabel, C. A. Search for Related Content PubMed PubMed Citation Articles by Laliberte, R. E. Articles by Gabel, C. A. Social Bookmarking                      What's this?

Glutathione S-Transferase Omega 1-1 Is a Target of Cytokine Release Inhibitory Drugs and May Be Responsible for Their Effect on Interleukin-1 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. Gabel

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-1 (IL-1) 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-1 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-1 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-1 posttranslational processing may be attributable to their interaction with GST Omega 1-1.

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