Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells
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| Authors: | Montgomery, A; Tam, F; Gursche, C; Cheneval, C; Besler, K; Enns, W; Manku, S; Rey, K; Hanson, PJ; Rose-John, S; McManus, BM; Choy, JC |
| Year: | 2021 |
| Journal: | Am. J. Physiol.-Cell Physiol. 320: C554-C565 Article Link (DOI) PubMed |
| Title: | Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells |
| Abstract: | IL-6 affects tissue protective/reparative and inflammatory properties of vascular endothelial cells (ECs). This cytokine can signal to cells through classic and trans-signaling mechanisms, which are differentiated based on the expression of IL-6 receptor (IL-6R) on the surface of target cells. The biological effects of these IL-6-signaling mechanisms are distinct and have implications for vascular pathologies. We have directly compared IL-6 classic and trans-signaling in ECs. Human ECs expressed IL-6R in culture and in situ in coronary arteries from heart transplants. Stimulation of human ECs with IL-6, to model classic signaling, triggered the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and ERK1/2 signaling pathways, whereas stimulation with IL-6 thorn sIL-6R, to model trans-signaling, triggered activation of STAT3, PI3K-Akt, and ERK1/2 pathways. IL-6 classic signaling reduced persistent injury of ECs in an allograft model of vascular rejection and inhibited cell death induced by growth factor withdrawal. When inflammatory effects were examined, IL-6 classic signaling did not induce ICAM or CCL2 expression but was sufficient to induce secretion of CXCL8 and support transmigration of neutrophil-like cells. IL-6 trans-signaling induced all inflammatory effects studied. Our findings show that IL-6 classic and trans-signaling have overlapping but distinct properties in controlling EC survival and inflammatory activation. This has implications for understanding the effects of IL-6 receptor-blocking therapies as well as for vascular responses in inflammatory and immune conditions. |
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