Induction of endothelial nitric oxide synthase expression by IL-17 in human vascular endothelial cells: implications for vascular remodeling in transplant vasculopathy.
IL-17 is a signature cytokine of Th17 cells, a recently described subset of effector CD4 T cells implicated in the development of several pathologies. We have examined the role of IL-17 in regulating endothelial NO synthase (eNOS) expression in human vascular endothelial cells (ECs) because of the key role of eNOS in determining the pathological outcome of immune-mediated vascular diseases. In cultured ECs, IL-17 increased expression of eNOS, eNOS phosphorylation at Ser(1177), and NO production. The induction of eNOS expression by IL-17 was prevented by the pharmacological inhibition of NF-κB, MEK, and JNK, as well as by small interfering RNA-mediated gene silencing of these signaling pathways. The expression of IL-17 was then examined by immunohistochemistry in human arteries affected by transplant vasculopathy (TV), a vascular condition that is a leading reflection of chronic heart transplant rejection. IL-17 was expressed by infiltrating leukocytes in the intima of arteries with TV, and the majority of IL-17-positive cells were T cells. The number of IL-17-positive cells was not correlated with the intima/media ratio, but was negatively correlated with the amount of luminal occlusion. There was also a significant positive correlation between the number of IL-17-positive cells and the density of eNOS-expressing luminal ECs in arteries with TV. Altogether, these findings show that IL-17 induces the expression of eNOS in human ECs and that this may facilitate outward expansion of arteries afflicted with TV.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Arthur C
AC
Liu
Martin
M
Lee
Bruce M
BM
McManus
Jonathan C
JC
Choy
D001158:Arteries; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D020381:Interleukin-17 / Q000032:analysis / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics*; D013601:T-Lymphocytes; D015533:Transcriptional Activation / Q000187:drug effects*; D014652:Vascular Diseases / Q000209:etiology / Q000276:immunology*
D020381:Interleukin-17; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III