Prostacyclin inhibits IFN-gamma-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner.
Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI(2)) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI(2) 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-gamma- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-gamma- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-alpha production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-gamma-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-gamma-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-gamma-signaling. We conclude that PGI(2) 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.
Strassheim
Derek
D
Pediatric Critical CareMedicine, University of Colorado Denver, Research Complex II, Room 6490, 12700 East 19th Avenue, Aurora, CO 80045, USA. Derek.Strassheim@ucdenver.edu
Riddle
Suzzette R
SR
Burke
Danielle L
DL
Geraci
Mark W
MW
Stenmark
Kurt R
KR
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000276:immunology / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D011464:Epoprostenol; D050880:p300-CBP Transcription Factors; D016285:Iloprost