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Prostacyclin Inhibits IFN--Stimulated Cytokine Expression by Reduced Recruitment of CBP/p300 to STAT1 in a SOCS-1-Independent Manner¹

Pediatric Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045

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-- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-- and IL-6-induced MCP-1, IL-8, RANTES, and TNF- production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN--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--signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The sources of funding for this work were National Institutes of Health Grants HL64917 (to M. Das, University of Colorado, Denver, CO) and HL57144-09, HL14985-33, P01 HL014985-35, and P50 HL084923-03 (to K.R.S.).

² Address correspondence and reprint requests to Dr. Derek Strassheim, Pediatric Critical Care Medicine, University of Colorado Denver, Research Complex II, Room 6490, 12700 East 19th Avenue, Aurora, CO 80045. E-mail address: Derek.Strassheim{at}ucdenver.edu

³ Abbreviations used in this paper: PAH, pulmonary arterial hypertension; CBP, CREB-binding protein; GAS, IFN--activated sequence; GPCR, G protein-coupled receptor; PGI₂, prostacyclin; PKA, protein kinase A; siRNA, small interfering RNA; SOCS, suppressor of cytokine signaling; TAD, transactivation domain.