Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner

Derek Strassheim, Suzzette R. Riddle, Danielle L. Burke, Mark W. Geraci, Kurt R. Stenmark

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-γ- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.

Original languageEnglish (US)
Pages (from-to)6981-6988
Number of pages8
JournalJournal of Immunology
Volume183
Issue number11
DOIs
StatePublished - Dec 1 2009

Fingerprint

Iloprost
Epoprostenol
Cytokines
Monocytes
Anti-Inflammatory Agents
Pulmonary Hypertension
Transcriptional Activation
Interleukin-6
p300-CBP Transcription Factors
Phosphorylation
Histone Acetyltransferases
Chemokine CCL5
Interleukin-8
Vascular Diseases
Leukocytes
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner. / Strassheim, Derek; Riddle, Suzzette R.; Burke, Danielle L.; Geraci, Mark W.; Stenmark, Kurt R.

In: Journal of Immunology, Vol. 183, No. 11, 01.12.2009, p. 6981-6988.

Research output: Contribution to journalArticle

Strassheim, Derek ; Riddle, Suzzette R. ; Burke, Danielle L. ; Geraci, Mark W. ; Stenmark, Kurt R. / Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner. In: Journal of Immunology. 2009 ; Vol. 183, No. 11. pp. 6981-6988.
@article{c63598ab9607454691b8637e8eb410a9,
title = "Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner",
abstract = "Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-γ- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.",
author = "Derek Strassheim and Riddle, {Suzzette R.} and Burke, {Danielle L.} and Geraci, {Mark W.} and Stenmark, {Kurt R.}",
year = "2009",
month = "12",
day = "1",
doi = "10.4049/jimmunol.0901045",
language = "English (US)",
volume = "183",
pages = "6981--6988",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner

AU - Strassheim, Derek

AU - Riddle, Suzzette R.

AU - Burke, Danielle L.

AU - Geraci, Mark W.

AU - Stenmark, Kurt R.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-γ- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.

AB - Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-γ- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.

UR - http://www.scopus.com/inward/record.url?scp=73349114919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73349114919&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0901045

DO - 10.4049/jimmunol.0901045

M3 - Article

C2 - 19915063

AN - SCOPUS:73349114919

VL - 183

SP - 6981

EP - 6988

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -