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The Journal of Immunology, 2002, 168: 3608-3616.
Copyright © 2002 by The American Association of Immunologists

IL-18-Binding Protein Expression by Endothelial Cells and Macrophages Is Up-Regulated During Active Crohn’s Disease1

Anne Corbaz*, Tessa ten Hove{dagger}, Suzanne Herren*, Pierre Graber*, Boris Schwartsburd{ddagger}, Ilana Belzer{ddagger}, Jillian Harrison*, Thomas Plitz*, Marie H. Kosco-Vilbois*, Soo-Hyun Kim§, Charles A. Dinarello§, Daniela Novick, Sander van Deventer{dagger} and Yolande Chvatchko2,*

* Department of Experimental Biology and Pharmacology, Serono Pharmaceutical Research Institute, Geneva, Switzerland; {dagger} Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands; {ddagger} InterPharma Laboratories, Nes Ziona, Israel; § Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262; and Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

The pathogenesis of Crohn’s disease (CD) remains under intense investigation. Increasing evidence suggests a role for mature IL-18 in the induction of proinflammatory cytokines and Th1 polarization in CD lesions. The aim of this study was to investigate the contribution of the IL-18-neutralizing (a and c) and non-neutralizing (b and d) isoforms of IL-18-binding protein (IL-18BP) during active CD. Intestinal endothelial cells and macrophages were the major source of IL-18BP within the submucosa, and this IL-18BP production was also found to be relevant to other types of endothelial cells (HUVEC) and macrophages (peripheral monocytes). IL-18BP messenger transcript and protein were significantly increased in surgically resected specimens from active CD compared with control patients, correlating with an up-regulation of IL-18. Analysis of the expression of the four IL-18BP isoforms as well as being free or bound to IL-18 was reported and revealed that unbound IL-18BP isoforms a and c and inactive isoform d were present in specimens from active CD and control patients while isoform b was not detected. IL-18/IL-18BP complex was also detected. Interestingly, although most was complexed, free mature IL-18 could still be detected in active CD specimens even in the presence of the IL-18BP isoform a/c. These results demonstrate that the appropriate neutralizing isoforms are present in the intestinal tissue of patients with active CD and highlights the complexity of IL-18/IL-18BP biology.




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