Intestinal epithelial cell up-regulation of LY6 molecules during colitis results in enhanced chemokine secretion.
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-gamma. 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.
Flanagan
Ken
K
Department of Pathology, Genentech, South San Francisco, CA 94080, USA.
Modrusan
Zora
Z
Cornelius
Jennine
J
Chavali
Arvind
A
Kasman
Ian
I
Komuves
Laszlo
L
Mo
Lian
L
Diehl
Lauri
L
D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002461:Cell Line, Transformed; D018925:Chemokines / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis / Q000502:physiology; D003092:Colitis / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D005810:Multigene Family / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
D000950:Antigens, Ly; D018925:Chemokines; C526827:Ly6 protein, mouse; D002784:Cholesterol