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Abstract
The Muc-1 oncoprotein is a tumor-associated mucin often overexpressed in pancreatic cancer. We report that knockout of Muc-1 reduced the degree of pancreatic inflammation that resulted from infection with Coxsackievirus B3 (CVB3) in a mouse model. CVB3-infected Muc-1-deficient (Muc-1KO) mice had significantly reduced infiltration of macrophages into the murine pancreas. We found that Muc-1 signaling through NF-κB increased expression of ICAM-1, a pro-inflammatory mediator that recruits macrophages. Further investigation revealed that bone marrow derived macrophages (BMDM) from the Muc-1KO mice exhibited defective migration properties, in part due to low expression of the C-C motif chemokine receptor (CCR2) and the integrin Very Late Antigen 4 (VLA-4). The results presented here provide novel insight into the role of Muc-1 in regulating the inflammatory response and the cellular microenvironment in pancreatitis.
Highlights
Mucins are heavily glycosylated proteins that give the mucosa viscous gel-forming properties, and contribute to the structural organization of secretory epithelia
Similar to previous studies[13,14,16,17], we found that WT mice infected with Coxsackievirus B3 (CVB3) display severe inflammatory pancreatitis that was evident by day 4 post-infection, peaked at days 6–8, and was resolved with evidence of some fatty replacement by day 21 (Fig. 1B upper panels)
As inflammatory monocytes are recruited to most organs, where they give rise to proinflammatory macrophages in response to tissue damage, we evaluated the macrophage population in these animals during the course of infection, production of pancreatitis, and resolution
Summary
Mucins are heavily glycosylated proteins that give the mucosa viscous gel-forming properties, and contribute to the structural organization of secretory epithelia. We explored potential functions of Muc-1 in inflammation that accompanies CVB3-induced pancreatitis, and discovered that mice lacking Muc-1 showed a dramatically attenuated inflammatory and tissue remodeling reaction to virus infection. Muc-1-deficient mice exhibited defective migration properties, in part due to low expression of the chemokine receptor CCR2 and the integrin Very Late Antigen 4 (VLA-4). These results provide insight into the role of Muc[1] and its regulation of key inflammatory cells in virally-induced pancreatitis. These findings suggest that Muc[1] is a novel molecular target for intervening in cases of acute inflammatory pancreatitis
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