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Intestinal Epithelial Cell Up-Regulation of LY6 Molecules during Colitis Results in Enhanced Chemokine Secretion

Ken Flanagan^*, Zora Modrusan, Jennine Cornelius^*, Arvind Chavali^*, Ian Kasman^*, Laszlo Komuves^*, Lian Mo^* and Lauri Diehl^1,*

^* Department of Pathology and Department of Molecular Biology, Genentech, South San Francisco, CA 94080

In the healthy colon, intestinal epithelial cells (IEC) form a physical barrier separating the myriad of gut Ags from the cells of the immune system. Simultaneously, IEC use several mechanisms to actively maintain immunologic tolerance to nonpathogenic Ags, including commensal bacteria. However, during inflammatory bowel disease (IBD), the line of defense provided by IEC is breached, resulting in uncontrolled immune responses. As IEC are a principal mediator of immune responses in the gut, we were interested in discerning the gene expression pattern of IEC during development and progression of IBD. Laser capture microdissection and microarray analysis were combined to identify the LY6 superfamily as strongly up-regulated genes in inflamed IEC of the colon in two models of murine colitis. Surface expression of LY6A and LY6C on IEC is induced by several cytokines present within the colitic gut, including IL-22 and IFN-. Furthermore, cross-linking of LY6C results in production of a number of chemokines which are known to be involved in the immunopathogenesis of IBD. Increased chemokine production was cholesterol dependent, suggesting a role for lipid raft structures in the mechanism. As such, LY6 molecules represent novel targets to down-regulate chemokine expression in the colon and limit subsequent inflammation associated with IBD.

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 Address correspondence and reprint requests to Dr. Lauri Diehl, Genentech, 1 DNA Way, MS 72B, South San Francisco, CA 94080. E-mail address: Diehl.Lauri{at}gene.com

² Abbreviations used in this paper: IEC, intestinal epithelial cell; IBD, inflammatory bowel disease; KLH, keyhole limpet hemocyanin; LCM, laser capture microscopy; siRNA, small interfering RNA.

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