Molecular fingerprint of interferon-gamma signaling in unstable angina

Background-Activation of circulating monocytes in patients with acute coron ary syndromes may reflect exposure to. bacterial products or stimulation by cytokines such as IFN-gamma. IFN-gamma induces phosphorylation and nuclear translocation of transcription factor STAT-I, which initiates a specific p rogram of gene induction. To explore whether monocyte activation is IFN-gam ma driven, patients with unstable (UA) or stable angina (SA) were compared for nuclear translocation of STAT-I complexes and upregulation of IFN-gamma -inducible genes CD64 and IP-10. Methods and Results-Peripheral blood mononuclear cells were stained for exp ression of CD64 on CD14(+) monocytes and analyzed by PCR for transcription of IP-10. Expression of CD64 was significantly increased in patients with U A. Monocytes from UA patients remained responsive to IFN-gamma in vitro, wi th accelerated transcriptional competency of CD64. IP-10-specific sequences were spontaneously detectable in 82% of the UA patients and 15% of SA pati ents (P<0.001). Most importantly, STAT-1 complexes were found in nuclear ex tracts prepared from freshly isolated monocytes of patients with UA, which provides compelling evidence for IFN-<gamma> signaling in vivo. Conclusions-Monocytes from UA patients exhibit a molecular fingerprint of r ecent IFN-gamma triggering, such as nuclear translocation of STAT-I complex es and upregulation of IFN-gamma -inducible genes CD64 and IP-10, which sug gests that monocytes are activated, at least in part, by IFN-gamma. IFN-gam ma may derive from stimulated T lymphocytes, which implicates specific immu ne responses in the pathogenesis of acute coronary syndromes.