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P057. Enhanced expression of CXCL10 in inflammatory bowel disease – potential role of mucosal Toll-like receptor 3 stimulation


A.E. Østvik1, N. Nilsen2, A.v.B. Granlund2, S.H. Torp3, A. Flatberg2, H.L. Waldum1, T. Espevik2, J.K. Damås4, A.K. Sandvik3

1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Department of Gastroenterology, St. Olav's University Hospital, Trondheim, Norway, Trondheim, Norway; 2Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 3Department of Laboratory Medicine, Children and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olav's University Hospital, Trondheim, Norway, Trondheim, Norway; 4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Department of Infectious Diseases, St. Olav's University Hospital, Trondheim, Norway, Trondheim, Norway



Background: We explored the gene expression of 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 most upregulated genes. CXCL10 is an important chemoattractant for activated T‑lymphocytes and T‑lymphocyte migration, and its regulation may play an important role in the pathogenesis of IBD. We therefore undertook this study to examine the roles of CXCL10 in UC and CD.

Methods: A microarray gene expression analysis was done on colonic biopsies (n = 133) from patients with IBD, using Illumina Bead Chip technology. A subset of colonic biopsies was examined by histology and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from the same clinical material, as well as the colonic epithelial cell lines HT-29 and SW 620, were studied to explore their secretion of CXCL10 in response to pattern recognition receptor (PRR) ligands.

Results: Gene expression levels of CXCL10 and CXCR3 were significantly upregulated in biopsies from active UC and CD, compared to patients with inactive disease and healthy controls. Immunohistochemistry demonstrated that CXCL10 was mainly localized to the mucosal epithelial cells, and we found significantly increased CXCL10 staining in active IBD vs controls. CXCR3 positive cells were scattered in the submucosa. In vitro, CXCL10 was secreted from HT-29 and SW 620 cells in response to the Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C). Poly I:C also markedly induced CXCL10 in PBMCs from both IBD patients and controls. However, the spontaneous release of CXCL10 in PBMCs was significantly attenuated in UC patients comparing cells from CD and healthy controls, and was inversely correlated to serum levels of CXCL10 in these patients.

Conclusions: Herein we identify CXCL10 and CXCR3 as profoundly upregulated genes in colonic mucosa of active IBD. We also show decreased spontaneous secretion of CXCL10 in PBMCs from UC patients, possibly reflecting cellular anergy after a marked in vivo activation in these patients. By exploring the effects of various PRR-ligands, we found that TLR3-ligand markedly increased secretion of CXCL10 in epithelial cells, suggesting a possible role for TLR3 in mediating enhanced CXCL10 secretion in mucosal epithelial cells from IBD patients.