Journal
CYTOKINE
Volume 113, Issue -, Pages 238-247Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2018.07.011
Keywords
IL-27; The purinergic pathway; HIF1 alpha; VEGFA; Human macrophages; Diabetic retinopathy
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Human macrophages produce vascular endothelial growth factor A (VEGFA) for angiogenesis in diabetic retinopathy (DR). The regulatory function of IL-27 on human macrophages is not well understood. In particular, the effect of IL-27 on VEGFA response in human macrophages has not been investigated. We find that IL-27 suppresses VEGFA mRNA expression as well as protein secretion by human macrophages. The synergistic action of purinergic signaling and activation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) induces VEGFA production in a positive feedback loop. IL-27 signaling in human macrophages disrupts this positive feedback loop thus suppresses VEGFA production. Blockade of IL-27 signaling with a JAK2 antagonist reverses this downregulatory effect on HIF-la and partially blocks the inhibitory effect on VEGFA production. Lastly, DR patient macrophages have a higher propensity to produce VEGFA and this is amplified by an in vitro challenge with the pro-inflammatory cytokine IL-1 beta suppresses VEGFA production by DR patient macrophages even in the presence of IL-1 beta challenge indicating a potential therapeutic use of IL-27 in the clinic.
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