CYLD Enhances Severe Listeriosis by Impairing IL-6/STAT3-Dependent Fibrin Production
(2013) In PLoS Pathogens 9(6).- Abstract
- 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-kappa B, and tissue protective factors including fibrin. However, molecular pathways connecting NF-kappa B and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-kappa B-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... (More)
- 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-kappa B, and tissue protective factors including fibrin. However, molecular pathways connecting NF-kappa B and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-kappa B-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-kappa B-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-kappa B 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-kappa B/IL-6/STAT3 pathway and fibrin production. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3979218
- author
- Nishanth, Gopala ; Deckert, Martina ; Wex, Katharina ; Massoumi, Ramin LU ; Schweitzer, Katrin ; Naumann, Michael and Schlueter, Dirk
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Pathogens
- volume
- 9
- issue
- 6
- article number
- e1003455
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000321206600054
- scopus:84879534780
- pmid:23825949
- ISSN
- 1553-7366
- DOI
- 10.1371/journal.ppat.1003455
- language
- English
- LU publication?
- yes
- id
- c03f9ac6-4074-4c53-bed5-8b31f3fa2af7 (old id 3979218)
- date added to LUP
- 2016-04-01 10:52:23
- date last changed
- 2022-02-25 06:30:11
@article{c03f9ac6-4074-4c53-bed5-8b31f3fa2af7,
abstract = {{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-kappa B, and tissue protective factors including fibrin. However, molecular pathways connecting NF-kappa B and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-kappa B-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-kappa B-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-kappa B 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-kappa B/IL-6/STAT3 pathway and fibrin production.}},
author = {{Nishanth, Gopala and Deckert, Martina and Wex, Katharina and Massoumi, Ramin and Schweitzer, Katrin and Naumann, Michael and Schlueter, Dirk}},
issn = {{1553-7366}},
language = {{eng}},
number = {{6}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS Pathogens}},
title = {{CYLD Enhances Severe Listeriosis by Impairing IL-6/STAT3-Dependent Fibrin Production}},
url = {{https://lup.lub.lu.se/search/files/2201455/4362380.pdf}},
doi = {{10.1371/journal.ppat.1003455}},
volume = {{9}},
year = {{2013}},
}