Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells.
BACKGROUND
Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis.


RESULTS
Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion.


CONCLUSIONS
Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.
Eid
Raymond E
RE
Interdepartmental Program in Vascular Biology and Therapeutics and Department of Surgery, Yale University School of Medicine, New Haven, Conn., USA.
Rao
Deepak A
DA
Zhou
Jing
J
Lo
Sheng-fu L
SF
Ranjbaran
Hooman
H
Gallo
Amy
A
Sokol
Seth I
SI
Pfau
Steven
S
Pober
Jordan S
JS
Tellides
George
G
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000378:metabolism; D003324:Coronary Artery Disease / Q000150:complications / Q000276:immunology / Q000473:pathology*; D003331:Coronary Vessels / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014657:Vasculitis / Q000209:etiology* / Q000503:physiopathology; D000096743:Interferon gamma Receptor
D054357:Chemokine CXCL10; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D017471:Receptors, Interferon; D053722:Receptors, Interleukin-17; D053773:Transforming Growth Factor beta1; D000096743:Interferon gamma Receptor; C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; C508717:IL17A protein, human; C109985:IL17RA protein, human; C508600:IL6 protein, human