Activation of epithelial CD98 glycoprotein perpetuates colonic inflammation

Abstract

Anomalies in the regulation and function of integrins have been implicated in the etiology of various pathologic conditions, including inflammatory disorders such as irritable bowel disease. Several classes of cell surface glycoproteins such as CD98 have been shown to play roles in integrins-mediated events. Here, we investigated the role of CD98 in intestinal inflammation using both in vivo and in vitro approaches. We found that in Caco2-BBE monolayers and colonic tissues, expression of CD98 was upregulated by the proinflammatory cytokine, interferon gamma (INF c). Furthermore, CD98 was highly upregulated in colonic tissues from mice with active colitis induced by dextran sodium sulfate (DSS), but not in DSS-treated INF c À/À mice. Administration of an anti-CD98 antibody worsened DSS-induced colitis in mice but had no effect on untreated control mice. Finally, we used Caco2-BBE cell monolayers to model intestinal epithelial wound healing, and found that activation of epithelial CD98 in DSS-treated monolayers inhibited monolayer reconstitution, but had no affect on untreated control monolayers. Our data collectively indicate that (i) CD98 upregulation is mediated by INF c during intestinal inflammation and (ii) activation of epithelial CD98 protein aggravates intestinal inflammation by reducing intestinal epithelial reconstitution. Overall, our data suggest that epithelial CD98 plays an important role in the perpetuation of intestinal inflammation. Laboratory Investigation (2005) 85, 932-941.

CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

“…overexpression promoted colonic tumorigenesis in mouse models of CAC by aggravating intestinal inflammation, with increased IEC proliferation and induction of proinflammatory cytokines and chemokines crucially contributing to tumor progression (2). Our previous studies demonstrated upregulation of CD98 expression in cultured IECs stimulated with proinflammatory cytokines (19,21), in colonic tissues from mice with active colitis (17), and in colonic biopsies from IBD patients (21). We now provide direct evidence that IEC-specific CD98 overexpression aggravates intestinal inflammation in a mouse model of DSS-induced colitis, accompanied by massively increased production of proinflammatory cytokines and chemokines.…”

“…15), and various human neoplasms (16). Upregulation of CD98 has also been observed in intestinal inflammation in vitro and in vivo (17)(18)(19)(20)(21). Despite the increasing number of studies on this molecule, the potential pathogenetic role of CD98 in CRC, particularly when associated to chronic inflammation, has yet to be explored.…”

Use of Single-Chain Antibody Derivatives for Targeted Drug Delivery

“…CD98 is a cell surface receptor found to be overexpressed in colonic tissues of mice with colitis, on the surface of intestinal T cells (CD4 + T cells and CD8 + T cells) and B cells of patients with inflammatory bowel disease (IBD) and in intestinal macrophages (34)(35)(36). As CD98 plays an important role in progression of IBD, it can serve as a potential target for therapy of IBD patients.…”

Recognition of Endogenous Ligands by C-Type Lectins:Interaction of Serum Mannan-binding Protein with Tumor-associated Oligosaccharide Epitopes

“…Utilizing an MBP affinity column, we succeeded in the isolation of the major MBP-ligand glycoproteins from cell lysates, and identified them as CD26/dipeptidylpeptidase IV (DPPIV) (110 kDa) (43) and CD98 heavy chain (CD98hc)/4F2hc (82 kDa) (44). PNGase F and endo β-N-acetylglucosaminidase H digestion of these proteins together with MBP-blot analysis suggested that CD26 contained complex-type N-glycans (MLO) that appear to mediate the MBP binding, whereas the CD98 heavy chain consisted almost exclusively of high-mannose type or hybrid type glycans.…”