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

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.

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.

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.

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.