Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation

Arihiro Kano, Michael J. Wolfgang, Qian Gao, Joerg Jacoby, Gui Xuan Chai, William Hansen, Yoshiki Iwamoto, Jordan S. Pober, Richard A. Flavell, Xin Yuan Fu

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3 E-/- ). STAT3 E-/- mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3 E-/- mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

Original languageEnglish
Pages (from-to)1517-1525
Number of pages9
JournalJournal of Experimental Medicine
Volume198
Issue number10
DOIs
Publication statusPublished - Nov 17 2003
Externally publishedYes

Fingerprint

Endotoxins
Endothelium
Endothelial Cells
Inflammation
Lipopolysaccharides
Anti-Inflammatory Agents
Cytokines
STAT3 Transcription Factor
Transforming Growth Factors
Septic Shock
Aspartate Aminotransferases
Alanine Transaminase
Cardiac Myocytes
Knockout Mice
Interleukin-10
Interferons
Hepatocytes
Immunity
Leukocytes
Serum

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Kano, A., Wolfgang, M. J., Gao, Q., Jacoby, J., Chai, G. X., Hansen, W., ... Fu, X. Y. (2003). Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation. Journal of Experimental Medicine, 198(10), 1517-1525. https://doi.org/10.1084/jem.20030077

Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation. / Kano, Arihiro; Wolfgang, Michael J.; Gao, Qian; Jacoby, Joerg; Chai, Gui Xuan; Hansen, William; Iwamoto, Yoshiki; Pober, Jordan S.; Flavell, Richard A.; Fu, Xin Yuan.

In: Journal of Experimental Medicine, Vol. 198, No. 10, 17.11.2003, p. 1517-1525.

Research output: Contribution to journalArticle

Kano, A, Wolfgang, MJ, Gao, Q, Jacoby, J, Chai, GX, Hansen, W, Iwamoto, Y, Pober, JS, Flavell, RA & Fu, XY 2003, 'Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation', Journal of Experimental Medicine, vol. 198, no. 10, pp. 1517-1525. https://doi.org/10.1084/jem.20030077
Kano, Arihiro ; Wolfgang, Michael J. ; Gao, Qian ; Jacoby, Joerg ; Chai, Gui Xuan ; Hansen, William ; Iwamoto, Yoshiki ; Pober, Jordan S. ; Flavell, Richard A. ; Fu, Xin Yuan. / Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation. In: Journal of Experimental Medicine. 2003 ; Vol. 198, No. 10. pp. 1517-1525.
@article{ee0f0f2aed7c4a58a75d211870408fd4,
title = "Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation",
abstract = "Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3 E-/- ). STAT3 E-/- mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3 E-/- mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.",
author = "Arihiro Kano and Wolfgang, {Michael J.} and Qian Gao and Joerg Jacoby and Chai, {Gui Xuan} and William Hansen and Yoshiki Iwamoto and Pober, {Jordan S.} and Flavell, {Richard A.} and Fu, {Xin Yuan}",
year = "2003",
month = "11",
day = "17",
doi = "10.1084/jem.20030077",
language = "English",
volume = "198",
pages = "1517--1525",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "10",

}

TY - JOUR

T1 - Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inflammation

AU - Kano, Arihiro

AU - Wolfgang, Michael J.

AU - Gao, Qian

AU - Jacoby, Joerg

AU - Chai, Gui Xuan

AU - Hansen, William

AU - Iwamoto, Yoshiki

AU - Pober, Jordan S.

AU - Flavell, Richard A.

AU - Fu, Xin Yuan

PY - 2003/11/17

Y1 - 2003/11/17

N2 - Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3 E-/- ). STAT3 E-/- mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3 E-/- mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

AB - Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3 E-/- ). STAT3 E-/- mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3 E-/- mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

UR - http://www.scopus.com/inward/record.url?scp=10744231991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744231991&partnerID=8YFLogxK

U2 - 10.1084/jem.20030077

DO - 10.1084/jem.20030077

M3 - Article

VL - 198

SP - 1517

EP - 1525

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 10

ER -