CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production.
The facultative intracellular bacterium Listeria monocytogenes (Lm) may cause severe infection in humans and livestock. Control of acute listeriosis is primarily dependent on innate immune responses, which are strongly regulated by NF-κB, and tissue protective factors including fibrin. However, mole...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS Pathogens |
Online Access: | http://europepmc.org/articles/PMC3695090?pdf=render |
id |
doaj-605379d064a048158b6fd15890ec59cf |
---|---|
record_format |
Article |
spelling |
doaj-605379d064a048158b6fd15890ec59cf2020-11-24T22:09:33ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0196e100345510.1371/journal.ppat.1003455CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production.Gopala NishanthMartina DeckertKatharina WexRamin MassoumiKatrin SchweitzerMichael NaumannDirk SchlüterThe facultative intracellular bacterium Listeria monocytogenes (Lm) may cause severe infection in humans and livestock. Control of acute listeriosis is primarily dependent on innate immune responses, which are strongly regulated by NF-κB, and tissue protective factors including fibrin. However, molecular pathways connecting NF-κB and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-κB-dependent immune responses, regulated these protective host responses in murine listeriosis. Upon high dose systemic infection, all C57BL/6 Cyld(-/-) mice survived, whereas 100% of wildtype mice succumbed due to severe liver pathology with impaired pathogen control and hemorrhage within 6 days. Upon in vitro infection with Lm, CYLD reduced NF-κB-dependent production of reactive oxygen species, interleukin (IL)-6 secretion, and control of bacteria in macrophages. Furthermore, Western blot analyses showed that CYLD impaired STAT3-dependent fibrin production in cultivated hepatocytes. Immunoprecipitation experiments revealed that CYLD interacted with STAT3 in the cytoplasm and strongly reduced K63-ubiquitination of STAT3 in IL-6 stimulated hepatocytes. In addition, CYLD diminished IL-6-induced STAT3 activity by reducing nuclear accumulation of phosphorylated STAT3. In vivo, CYLD also reduced hepatic STAT3 K63-ubiquitination and activation, NF-κB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis. In vivo neutralization of IL-6 by anti-IL-6 antibody, STAT3 by siRNA, and fibrin by warfarin treatment, respectively, demonstrated that IL-6-induced, STAT3-mediated fibrin production significantly contributed to protection in Cyld(-/-) mice. In addition, in vivo Cyld siRNA treatment increased STAT3 phosphorylation, fibrin production, pathogen control and survival of Lm-infected WT mice illustrating that therapeutic inhibition of CYLD augments the protective NF-κB/IL-6/STAT3 pathway and fibrin production.http://europepmc.org/articles/PMC3695090?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gopala Nishanth Martina Deckert Katharina Wex Ramin Massoumi Katrin Schweitzer Michael Naumann Dirk Schlüter |
spellingShingle |
Gopala Nishanth Martina Deckert Katharina Wex Ramin Massoumi Katrin Schweitzer Michael Naumann Dirk Schlüter CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. PLoS Pathogens |
author_facet |
Gopala Nishanth Martina Deckert Katharina Wex Ramin Massoumi Katrin Schweitzer Michael Naumann Dirk Schlüter |
author_sort |
Gopala Nishanth |
title |
CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. |
title_short |
CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. |
title_full |
CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. |
title_fullStr |
CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. |
title_full_unstemmed |
CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. |
title_sort |
cyld enhances severe listeriosis by impairing il-6/stat3-dependent fibrin production. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2013-01-01 |
description |
The facultative intracellular bacterium Listeria monocytogenes (Lm) may cause severe infection in humans and livestock. Control of acute listeriosis is primarily dependent on innate immune responses, which are strongly regulated by NF-κB, and tissue protective factors including fibrin. However, molecular pathways connecting NF-κB and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-κB-dependent immune responses, regulated these protective host responses in murine listeriosis. Upon high dose systemic infection, all C57BL/6 Cyld(-/-) mice survived, whereas 100% of wildtype mice succumbed due to severe liver pathology with impaired pathogen control and hemorrhage within 6 days. Upon in vitro infection with Lm, CYLD reduced NF-κB-dependent production of reactive oxygen species, interleukin (IL)-6 secretion, and control of bacteria in macrophages. Furthermore, Western blot analyses showed that CYLD impaired STAT3-dependent fibrin production in cultivated hepatocytes. Immunoprecipitation experiments revealed that CYLD interacted with STAT3 in the cytoplasm and strongly reduced K63-ubiquitination of STAT3 in IL-6 stimulated hepatocytes. In addition, CYLD diminished IL-6-induced STAT3 activity by reducing nuclear accumulation of phosphorylated STAT3. In vivo, CYLD also reduced hepatic STAT3 K63-ubiquitination and activation, NF-κB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis. In vivo neutralization of IL-6 by anti-IL-6 antibody, STAT3 by siRNA, and fibrin by warfarin treatment, respectively, demonstrated that IL-6-induced, STAT3-mediated fibrin production significantly contributed to protection in Cyld(-/-) mice. In addition, in vivo Cyld siRNA treatment increased STAT3 phosphorylation, fibrin production, pathogen control and survival of Lm-infected WT mice illustrating that therapeutic inhibition of CYLD augments the protective NF-κB/IL-6/STAT3 pathway and fibrin production. |
url |
http://europepmc.org/articles/PMC3695090?pdf=render |
work_keys_str_mv |
AT gopalanishanth cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT martinadeckert cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT katharinawex cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT raminmassoumi cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT katrinschweitzer cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT michaelnaumann cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction AT dirkschluter cyldenhancesseverelisteriosisbyimpairingil6stat3dependentfibrinproduction |
_version_ |
1725811303154450432 |