Enhanced expression of CXCL10 in inflammatory bowel disease: potential role of mucosal Toll-like receptor 3 stimulation.
BACKGROUND
We explored the gene expression in colonic biopsies of active and inactive inflammatory bowel disease (IBD) in an extensive material of ulcerative colitis (UC) and Crohn's disease (CD). The chemokine CXCL10 and its receptor CXCR3 were among the upregulated genes. This study examined the expression of CXCL10 and the mechanisms for its release in patients with UC or CD and in intestinal epithelial cell (IEC) lines.


METHODS
A microarray gene expression analysis was done on colonic biopsies (n = 133) from patients with IBD. Biopsies were studied with immunohistochemistry for CXCL10 and CXCR3 expression. Mechanisms for CXCL10 release in peripheral blood mononuclear cells (PBMCs) and in the colonic epithelial cell lines HT-29 and SW620 were studied upon pattern recognition receptor (PRR) stimulation.


RESULTS
CXCL10 and CXCR3 mRNA abundances were increased in biopsies from active UC and CD compared to inactive disease and controls. CXCL10 was mainly localized to mucosal epithelial cells, with increased immunostaining in active IBD. CXCR3-positive cells were scattered in the lamina propria. CXCL10 was secreted from the colonic epithelial cell lines in response to the Toll-like receptor 3 (TLR3) ligand polyinosinic: polycytidylic acid (poly(I:C)). This ligand also induced a marked release of CXCL10 in PBMCs from IBD patients and controls.


CONCLUSIONS
We identified CXCL10 and CXCR3 as upregulated genes in colonic mucosa in active IBD. The TLR3-ligand poly(I:C) markedly increased release of CXCL10 in colonic epithelial cell lines, suggesting a TLR3-mediated CXCL10 release from mucosal epithelial cells in IBD patients.
Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway.
Ann E
AE
Ostvik
Atle V B
AV
Granlund
Marit
M
Bugge
Nadra J
NJ
Nilsen
Sverre H
SH
Torp
Helge L
HL
Waldum
Jan K
JK
Damås
Terje
T
Espevik
Arne K
AK
Sandvik
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D016018:Least-Squares Analysis; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011070:Poly I-C / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation
D015415:Biomarkers; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011070:Poly I-C