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-Inducible Lysosomal Thiol Reductase Expression by Inflammatory Cytokines1
* Department of Cell Biology and
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
IFN-
-inducible lysosomal thiol reductase (GILT), which plays a role in MHC class II-restricted processing and presentation of Ags containing disulfide bonds, can be induced in various cell types by the cytokine IFN-. APCs, including circulating macrophages, constitutively express high levels of GILT, although the pathways regulating its expression in these cells have not been characterized. In this study, we used the promonocytic cell line THP-1, an established model for monocyte to macrophage differentiation, to investigate the induction of GILT upon exposure to bacteria. We show that contact with LPS or intact Escherichia coli causes THP-1 cells to undergo programmed differentiation, characterized by adhesion, cytokine secretion, and up-regulation of Ag processing and presentation components, including GILT. Unlike GILT induction in response to IFN- treatment, induction by bacteria is dependent on new protein synthesis, NF-
B signaling, and secretion of the inflammatory cytokines TNF and IL-1
. Furthermore, we show that both cytokines are sufficient for GILT induction in the absence of a microbial stimulus. The majority of GILT synthesized by differentiated THP-1 cells is secreted as the precursor form rather than being transported to, and maturing in, lysosomes, suggesting a novel role for GILT in cells of the macrophage lineage.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R37-AI23081 and the Howard Hughes Medical Institute. R.L.L. was supported by grants from the Natural Sciences and Engineering Research Council of Canada and Le Fonds Québécois de Recherche sur la Nature et les Technologies.
2 Address correspondence and reprint requests to Dr. Peter Cresswell, Section of Immunobiology, Yale University School of Medicine, P.O. Box 208011, New Haven, CT 06520-8011. E-mail address: peter.cresswell{at}yale.edu
3 Abbreviation used in this paper: GILT, IFN--inducible lysosomal thiol reductase.
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