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Mucin-1 is required for Coxsackie Virus B3-induced inflammation in pancreatitis.

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-1^KO) mice had significantly reduced infiltration of macrophages into the murine pancreas. We found that Muc-1 signaling through NF-?B increased expression of ICAM-1, a pro-inflammatory mediator that recruits macrophages. Further investigation revealed that bone marrow derived macrophages (BMDM) from the Muc-1^KO 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.

SUBMITTER: Liu X

PROVIDER: S-EPMC6650496 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Mucin-1 is required for Coxsackie Virus B3-induced inflammation in pancreatitis.

Liu Xiang X Clemens Dahn L DL Grunkemeyer James A JA Price Jeffrey D JD O'Connell Kelly K Chapman Nora M NM Storz Peter P Wen Haitao H Cox Jesse L JL Reid Whitney L WL Hollingsworth Michael A MA Thayer Sarah S

Scientific reports 20190723 1

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-1<sup>KO</sup>) 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 recruit ...[more]

PMID: 31337812

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Project description:Objective:Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation. Methods:A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were exposed to PQ in dose-dependent and time-dependent manners. Cell viability was detected by CCK-8 assays. The expression levels of MUC5B were examined by dot blot enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Western blotting was used to detect the levels of proteins in the MAPK and NF-?B pathways. Inflammatory factors in the cell culture medium were measured by ELISA. NF-?B and MAPK pathway inhibitors and MUC5B siRNA (siMUC5B) were used to determine the function of MUC5B. Finally, N-acetyl-cysteine (NAC) was added and its regulatory effect on the MAPK-NF-?B-MUC5B pathway was examined in PQ-induced cell inflammation. Results:MUC5B was significantly upregulated accompanying the increases in TNF-? and IL-6 secretion following PQ treatment in mouse and also in A549 cells after treatment with 50??M PQ at 24 hours. Furthermore, MAPK and NF-?B pathway inhibitors could dramatically decrease the expression of MUC5B and the secretion of TNF-? and IL-6. Importantly, siMUC5B could significantly attenuate the secretion of TNF-? and IL-6 induced by PQ. As expected, the addition of NAC efficiently suppresses the TNF-? and IL-6 secretion stimulated from PQ and also downregulated ERK, JNK, and p65 phosphorylation (ERK/JNK MAPK and NF-?B pathways) as well as MUC5B expression. Conclusion:Our findings suggest that MUC5B participates in the process of PQ-induced cell inflammation and is downstream of the NF-?B and MAPK pathways. NAC can attenuate PQ-induced cell inflammation at least in part by suppressing the MAPK-NF-?B-MUC5B pathway. These results nominate MUC5B as a new biomarker and therapeutic target for PQ-induced lung inflammation.

Dataset Information

Mucin-1 is required for Coxsackie Virus B3-induced inflammation in pancreatitis.

Publications

Mucin-1 is required for Coxsackie Virus B3-induced inflammation in pancreatitis.

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