Molecular Fingerprint of Interferon-&ggr; Signaling in Unstable Angina

BackgroundActivation of circulating monocytes in patients with acute coronary syndromes may reflect exposure to bacterial products or stimulation by cytokines such as IFN-&ggr;. IFN-&ggr; induces phosphorylation and nuclear translocation of transcription factor STAT-1, which initiates a specific program of gene induction. To explore whether monocyte activation is IFN-&ggr; driven, patients with unstable (UA) or stable angina (SA) were compared for nuclear translocation of STAT-1 complexes and upregulation of IFN-&ggr;-inducible genes CD64 and IP-10. Methods and ResultsPeripheral blood mononuclear cells were stained for expression of CD64 on CD14+ monocytes and analyzed by PCR for transcription of IP-10. Expression of CD64 was significantly increased in patients with UA. Monocytes from UA patients remained responsive to IFN-&ggr; in vitro, with accelerated transcriptional competency of CD64. IP-10-specific sequences were spontaneously detectable in 82% of the UA patients and 15% of SA patients (P <0.001). Most importantly, STAT-1 complexes were found in nuclear extracts prepared from freshly isolated monocytes of patients with UA, which provides compelling evidence for IFN-&ggr; signaling in vivo. ConclusionsMonocytes from UA patients exhibit a molecular fingerprint of recent IFN-&ggr; triggering, such as nuclear translocation of STAT-1 complexes and upregulation of IFN-&ggr;-inducible genes CD64 and IP-10, which suggests that monocytes are activated, at least in part, by IFN-&ggr;. IFN-&ggr; may derive from stimulated T lymphocytes, which implicates specific immune responses in the pathogenesis of acute coronary syndromes.

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