title: An inflammatory pathway of IFN-gamma production in coronary atherosclerosis.
abstract: Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-gamma-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-gamma and IFN-gamma-inducible chemokines, defining an IFN-gamma axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-gamma axis, but not that of IL-18. Activation of the IFN-gamma axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-gamma and IFN-gamma-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-gamma in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-gamma secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Ranjbaran
authors.forename: Seth I
authors.initials: SI
authors.lastname: Sokol
authors.forename: Amy
authors.initials: A
authors.lastname: Gallo
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Eid
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Iakimov
authors.forename: Alessio
authors.initials: A
authors.lastname: D'Alessio
authors.forename: John R
authors.initials: JR
authors.lastname: Kapoor
authors.forename: Shamsuddin
authors.initials: S
authors.lastname: Akhtar
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howes
authors.forename: Mihaela
authors.initials: M
authors.lastname: Aslan
authors.forename: Steven
authors.initials: S
authors.lastname: Pfau
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D000368:Aged; D001167:Arteritis / Q000276:immunology; D003324:Coronary Artery Disease / Q000276:immunology* / Q000401:mortality*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism*; D018664:Interleukin-12 / Q000097:blood / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism; D008222:Lymphokines / Q000097:blood; D008297:Male; D008875:Middle Aged; D015846:Monokines / Q000097:blood; D011379:Prognosis; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D008222:Lymphokines; D015846:Monokines; D018664:Interleukin-12; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases