A Role for Leucine-Rich α2-Glycoprotein in Leukocyte Trafficking and Mucosal Inflammation in Inflammatory Bowel Disease.

Background: Leucine-rich α2-glycoprotein (LRG) has been identified as a disease activity marker that reflects pathology of inflammatory diseases including inflammatory bowel disease (IBD). Whereas LRG was reported to modulate transforming growth factor beta-1 (TGF-β) signaling, the role of LRG in inflammatory diseases has not been fully clarified. Here we investigated the role of LRG in IBD.

Methods: First, we investigated the difference of pathologies between wild-type (WT) mice and LRG-deficient (LRG-/-) mice in dextran sodium sulfate (DSS)-induced experimental colitis. Next, we analyzed the role of LRG in colonic inflammation by using in vitro assay.

Results: Prompt LRG upregulation was detected on the colonic epithelial cells on day 1 post 3% DSS treatment. Body weight loss after DSS treatment was significantly less severe in LRG-/- mice than in WT mice. Histological examination disclosed that leukocyte infiltration in colonic tissue was attenuated in LRG-/- mice compared with WT mice on day 3. Interestingly, the expression of endoglin, one of adhesion molecules in vascular endothelial cells, was markedly elevated in WT mice on day 1 post-DSS treatment, but was not in LRG-/- mice. Anti-TGF-β antibody treatment in mice with DSS colitis revealed that TGF-β is critical for endoglin upregulation in endothelial cells. Importantly, recombinant LRG when added to the culture media enhanced TGF-β1-induced endoglin expression in endothelial cells and increased adherence of monocytes to endothelial cells.

Conclusions: Our data suggest that LRG accelerates the progression of colonic inflammation at least in part by enhancing leukocyte trafficking through the upregulation of TGF-β1-induced endoglin expression in vascular endothelial cells.