MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication

Mubeen Jafri, Bryan Donnelly, Monica McNeal, Richard Ward, Greg Tiao

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. Methods: Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. Results: Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. Conclusions: RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury.

Original languageEnglish (US)
Pages (from-to)192-201
Number of pages10
JournalSurgery
Volume142
Issue number2
DOIs
StatePublished - Aug 2007
Externally publishedYes

Fingerprint

Mitogens
Protein Kinases
Rotavirus
Rotavirus Infections
Wounds and Injuries
Transcription Factors
Extrahepatic Bile Ducts
Biliary Atresia
Biliary Tract
Cell Surface Receptors
p38 Mitogen-Activated Protein Kinases
Infection Control
Down-Regulation
Western Blotting
Phosphorylation
Infection

ASJC Scopus subject areas

  • Surgery

Cite this

MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication. / Jafri, Mubeen; Donnelly, Bryan; McNeal, Monica; Ward, Richard; Tiao, Greg.

In: Surgery, Vol. 142, No. 2, 08.2007, p. 192-201.

Research output: Contribution to journalArticle

Jafri, Mubeen ; Donnelly, Bryan ; McNeal, Monica ; Ward, Richard ; Tiao, Greg. / MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication. In: Surgery. 2007 ; Vol. 142, No. 2. pp. 192-201.
@article{1663ea82a92240fdb5fd676d00acc107,
title = "MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication",
abstract = "Background: Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. Methods: Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. Results: Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. Conclusions: RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury.",
author = "Mubeen Jafri and Bryan Donnelly and Monica McNeal and Richard Ward and Greg Tiao",
year = "2007",
month = "8",
doi = "10.1016/j.surg.2007.03.008",
language = "English (US)",
volume = "142",
pages = "192--201",
journal = "Surgery (United States)",
issn = "0039-6060",
publisher = "Mosby Inc.",
number = "2",

}

TY - JOUR

T1 - MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication

AU - Jafri, Mubeen

AU - Donnelly, Bryan

AU - McNeal, Monica

AU - Ward, Richard

AU - Tiao, Greg

PY - 2007/8

Y1 - 2007/8

N2 - Background: Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. Methods: Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. Results: Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. Conclusions: RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury.

AB - Background: Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. Methods: Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. Results: Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. Conclusions: RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury.

UR - http://www.scopus.com/inward/record.url?scp=34547612538&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547612538&partnerID=8YFLogxK

U2 - 10.1016/j.surg.2007.03.008

DO - 10.1016/j.surg.2007.03.008

M3 - Article

C2 - 17689685

AN - SCOPUS:34547612538

VL - 142

SP - 192

EP - 201

JO - Surgery (United States)

JF - Surgery (United States)

SN - 0039-6060

IS - 2

ER -