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TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway

Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is a serious systemic inflammatory reaction with organ dysfunction by infection. However, the function of TSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism of TSLP during...

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Autores principales: Han, Na-Ra, Moon, Phil-Dong, Kim, Hyung-Min, Jeong, Hyun-Ja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780965/
https://www.ncbi.nlm.nih.gov/pubmed/31480519
http://dx.doi.org/10.3390/jcm8091350
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author Han, Na-Ra
Moon, Phil-Dong
Kim, Hyung-Min
Jeong, Hyun-Ja
author_facet Han, Na-Ra
Moon, Phil-Dong
Kim, Hyung-Min
Jeong, Hyun-Ja
author_sort Han, Na-Ra
collection PubMed
description Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is a serious systemic inflammatory reaction with organ dysfunction by infection. However, the function of TSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism of TSLP during sepsis. Sepsis was induced by lipopolysaccharides (LPS) or Escherichia coli DH5α injection in mice. TSLP levels were measured in human subjects, mice, and macrophages. TSLP deficiency or murine double minute 2 (MDM2) deficiency was induced using siRNA or an MDM2 inhibitor, nutlin-3a. We found that TSLP levels were elevated in serum of patients and mice with sepsis. TSLP deficiency lowered liver damage and inflammatory cytokine levels in mice with sepsis. TSLP was produced by the MDM2/NF-κB signaling pathway in LPS-stimulated macrophages. TSLP downregulation by an MDM2 inhibitor, nutlin-3a, alleviated clinical symptoms and septic inflammatory responses. Pharmacological inhibition of TSLP level by cisplatin reduced the septic inflammatory responses. Altogether, the present results show that TSLP exacerbates septic inflammation via the MDM2 signaling pathway, suggesting that TSLP may be a potential target for the treatment of sepsis.
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spelling pubmed-67809652019-10-30 TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway Han, Na-Ra Moon, Phil-Dong Kim, Hyung-Min Jeong, Hyun-Ja J Clin Med Article Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is a serious systemic inflammatory reaction with organ dysfunction by infection. However, the function of TSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism of TSLP during sepsis. Sepsis was induced by lipopolysaccharides (LPS) or Escherichia coli DH5α injection in mice. TSLP levels were measured in human subjects, mice, and macrophages. TSLP deficiency or murine double minute 2 (MDM2) deficiency was induced using siRNA or an MDM2 inhibitor, nutlin-3a. We found that TSLP levels were elevated in serum of patients and mice with sepsis. TSLP deficiency lowered liver damage and inflammatory cytokine levels in mice with sepsis. TSLP was produced by the MDM2/NF-κB signaling pathway in LPS-stimulated macrophages. TSLP downregulation by an MDM2 inhibitor, nutlin-3a, alleviated clinical symptoms and septic inflammatory responses. Pharmacological inhibition of TSLP level by cisplatin reduced the septic inflammatory responses. Altogether, the present results show that TSLP exacerbates septic inflammation via the MDM2 signaling pathway, suggesting that TSLP may be a potential target for the treatment of sepsis. MDPI 2019-09-01 /pmc/articles/PMC6780965/ /pubmed/31480519 http://dx.doi.org/10.3390/jcm8091350 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Na-Ra
Moon, Phil-Dong
Kim, Hyung-Min
Jeong, Hyun-Ja
TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title_full TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title_fullStr TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title_full_unstemmed TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title_short TSLP Exacerbates Septic Inflammation via Murine Double Minute 2 (MDM2) Signaling Pathway
title_sort tslp exacerbates septic inflammation via murine double minute 2 (mdm2) signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780965/
https://www.ncbi.nlm.nih.gov/pubmed/31480519
http://dx.doi.org/10.3390/jcm8091350
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