Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production

Yeon Sook Choi, Hyun Jung Choi, Jeong Ki Min, Bo Jeong Pyun, Yong Sun Maeng, Hongryeol Park, Jihye Kim, Young Myeong Kim, Young-Guen Kwon

Research output: Contribution to journalArticle

171 Citations (Scopus)

Abstract

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.

Original languageEnglish
Pages (from-to)3117-3126
Number of pages10
JournalBlood
Volume114
Issue number14
DOIs
Publication statusPublished - 2009 Nov 19

Fingerprint

TNF Receptor-Associated Factor 6
Capillary Permeability
Nitric Oxide
Blood Vessels
Vascular Diseases
Interleukin-33
Intercellular Junctions
Nitric Oxide Synthase Type III
Endothelial cells
Interleukin-1
Ligation
Permeability
Skin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Choi, Yeon Sook ; Choi, Hyun Jung ; Min, Jeong Ki ; Pyun, Bo Jeong ; Maeng, Yong Sun ; Park, Hongryeol ; Kim, Jihye ; Kim, Young Myeong ; Kwon, Young-Guen. / Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. In: Blood. 2009 ; Vol. 114, No. 14. pp. 3117-3126.
@article{c06ba50fa27b488ca5fd96f1bcc5c634,
title = "Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production",
abstract = "Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.",
author = "Choi, {Yeon Sook} and Choi, {Hyun Jung} and Min, {Jeong Ki} and Pyun, {Bo Jeong} and Maeng, {Yong Sun} and Hongryeol Park and Jihye Kim and Kim, {Young Myeong} and Young-Guen Kwon",
year = "2009",
month = "11",
day = "19",
doi = "10.1182/blood-2009-02-203372",
language = "English",
volume = "114",
pages = "3117--3126",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "14",

}

Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. / Choi, Yeon Sook; Choi, Hyun Jung; Min, Jeong Ki; Pyun, Bo Jeong; Maeng, Yong Sun; Park, Hongryeol; Kim, Jihye; Kim, Young Myeong; Kwon, Young-Guen.

In: Blood, Vol. 114, No. 14, 19.11.2009, p. 3117-3126.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production

AU - Choi, Yeon Sook

AU - Choi, Hyun Jung

AU - Min, Jeong Ki

AU - Pyun, Bo Jeong

AU - Maeng, Yong Sun

AU - Park, Hongryeol

AU - Kim, Jihye

AU - Kim, Young Myeong

AU - Kwon, Young-Guen

PY - 2009/11/19

Y1 - 2009/11/19

N2 - Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.

AB - Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.

UR - http://www.scopus.com/inward/record.url?scp=70449475108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70449475108&partnerID=8YFLogxK

U2 - 10.1182/blood-2009-02-203372

DO - 10.1182/blood-2009-02-203372

M3 - Article

VL - 114

SP - 3117

EP - 3126

JO - Blood

JF - Blood

SN - 0006-4971

IS - 14

ER -