Vascular endothelial growth factor A (VEGF) is critical for vascular remodelling during tissue repair subsequent to inflammation or injury, but under pathological conditions, VEGF induces tissue damaging angiogenesis. Macrophages generate VEGF that supports angiogenesis, when they adapt to their environment and respond with a co-ordinated set of signals to promote or resolve inflammation. Depending on the stimulus, the phenotype of macrophage activation is broadly classified into M1 (NOS2(+)) and M2 (arginase-1(+)). In recent studies, IL-10, an anti-inflammatory cytokine that suppresses the M1 phenotype, has been shown to dampen the angiogenic switch and subsequent neovascularisation. However, as we show here, these effects are context dependent. In this study, we have demonstrated that IL-10 inhibits M1 bone marrow-derived macrophages (BMDMs) VEGF, stimulated by LPS/CGS21680 (adenosine A2A receptor agonist), but does not prevent VEGF production from M2 macrophages stimulated with prostaglandin E2 (PGE2). Furthermore, we show that hypoxic-conditioned BMDM generated VEGF was maintained in the presence of IL-10, but was suppressed when concomitantly stimulated with IFN-gamma. Finally, LPS/PGE2 generated an arginase-1(+) M2 macrophage that in addition to generating VEGF produced significant quantities of IL-10. Under these conditions, neither in IL-10 deficient macrophages nor following IL-10 neutralization was VEGF production affected. Our results indicate IL-10 suppressed M1 but not M2 derived VEGF, and that activation signals determined the influence of IL-10 on VEGF production. Consequently, therapies to suppress macrophage activation that as a result generate IL-10, or utilising IL-10 as a potential anti-angiogenic therapy, may result in a paradoxical support of neovascularisation and thus on-going tissue damage or aberrant repair.
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