Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells

Circulation. 2009 Mar 17;119(10):1424-32. doi: 10.1161/CIRCULATIONAHA.108.827618. Epub 2009 Mar 2.

Abstract

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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Chemokine CXCL10 / biosynthesis
  • Chemokine CXCL10 / metabolism
  • Coronary Artery Disease / complications
  • Coronary Artery Disease / immunology
  • Coronary Artery Disease / pathology*
  • Coronary Vessels / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation Mediators / metabolism*
  • Interferon gamma Receptor
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism
  • Interferon-gamma / physiology*
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / metabolism
  • Interleukin-17 / physiology*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / metabolism
  • Interleukins / pharmacology
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology*
  • Receptors, Interferon / antagonists & inhibitors
  • Receptors, Interferon / immunology
  • Receptors, Interleukin-17 / antagonists & inhibitors
  • Receptors, Interleukin-17 / immunology
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Vasculitis / etiology*
  • Vasculitis / physiopathology

Substances

  • CXCL10 protein, human
  • CXCL8 protein, human
  • Chemokine CXCL10
  • IL17A protein, human
  • IL17RA protein, human
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-6
  • Interleukin-8
  • Interleukins
  • Receptors, Interferon
  • Receptors, Interleukin-17
  • Transforming Growth Factor beta1
  • Interferon-gamma