IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn's disease.
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.
Corbaz
Anne
A
Department of Experimental Biology and Pharmacology, Serono Pharmaceutical Research Institute, Geneva, Switzerland.
ten Hove
Tessa
T
Herren
Suzanne
S
Graber
Pierre
P
Schwartsburd
Boris
B
Belzer
Ilana
I
Harrison
Jillian
J
Plitz
Thomas
T
Kosco-Vilbois
Marie H
MH
Kim
Soo-Hyun
SH
Dinarello
Charles A
CA
Novick
Daniela
D
van Deventer
Sander
S
Chvatchko
Yolande
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014471:Umbilical Veins; D015854:Up-Regulation / Q000276:immunology*
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein