P0002 PP MATRIX EXPANSION IN COELIAC DISEASE ??? A ROLE FOR IL-6?

Abstract

Introduction: The lesion of coeliac disease is associated with substantial increase in matrix volume 1. However, there is evidence that expression of matrix degrading metalloprotease (MMP)-1 and -3 is increased in active disease, particularly in the subepithelial region 2. This tendency to matrix degradation may be partially offset by simultaneous upregulation of tissue inhibitor of metalloprotease (TIMP)-1 2, but this leaves unexplained why overall matrix volume should increase. We have thus characterised expression of matrix proteoglycans, and studied the mucosal expression of known mediators of increased matrix production in coeliac disease compared to controls. Methods: We studied mucosal biopsies from 10 children with active coeliac disease compared to 10 histologically normal controls. Histochemical and immunohistochemical analysis was performed for the matrix components sulphated glycosaminoglycans (GAGs), heparan sulphate proteoglycans (HSPG), laminin and fibronectin, as well as for MMP-3. RT-PCR was used to characterise the mucosal expression of mRNA’s of potentially matrix-expanding mediators, including hepatocyte growth factor (HGF), its receptor c-Met, hypoxia-inducible factor -1á (HIF-1á) and interleukin-6 (IL-6). Mucosal localisation of HGF, c-Met and IL-6 was characterised by immunohistochemistry. Results: In contrast to active Crohn’s disease 3, there was no evidence of disruption of GAGs or other matrix within the lamina propria. Indeed their density was sometimes increased. However there was extensive loss of GAG and HSPG expression within the epithelial compartment, associated with focal expression of the GAG-degrading MMP-3 in the subepithelial region and around enterocytes. There was no evidence of increased expression of mRNA for HGF, c-Met or HIF-1á by RT-PCR, although modest increased expression of HGF and c-Met protein were seen on histochemistry. By contrast, there was striking increase of IL-6 mRNA and marked excess infiltration of IL-6+ mononuclear cells throughout the lamina propria. Conclusion: There is focal degradation of HSPG in the epithelial compartment, likely to be related to local MMP-3 production. This may contribute to increased intestinal leakage of albumin. Amongst recognised mediators of increased extracellular matrix production, IL-6 was the most strikingly increased at both mRNA and protein level in coeliac mucosa, and may be a target for specific therapy.