TY - JOUR

T1 - IL-20 activates human lymphatic endothelial cells causing cell signalling and tube formation

AU - Hammer, Troels

AU - Tritsaris, Katerina

AU - Hübschmann, Martin V

AU - Gibson, Josefine

AU - Nisato, Riccardo E

AU - Pepper, Michael S

AU - Dissing, Steen

PY - 2009/6

Y1 - 2009/6

N2 - IL-20 is an arteriogenic cytokine that remodels collateral networks in vivo, and plays a role in cellular organization. Here, we investigate its role in lymphangiogenesis using a lymphatic endothelial cell line, hTERT-HDLEC, which expresses the lymphatic markers LYVE-1 and podoplanin. Upon stimulation of hTERT-HDLEC with IL-20, we found an increase in the intracellular free calcium concentration, in Akt and eNOS phosphorylations as well as in perinuclear NO production. We found that eNOS phosphorylation and NO synthesis are highly dependent on the PI3K/Akt signalling pathway. We also found an IL-20 induced phosphorylation of Erk1/2 and mTOR, and using the MEK inhibitor PD98059 and mTOR complex inhibitor rapamycin we demonstrated the importance of these signalling pathways in IL-20-mediated proliferation. IL-20 triggered actin polymerization and morphological changes resulting in elongated cell structures, and in matrigels, IL-20 caused tube formations of hTERT-HDLEC in a PI3K- and mTOR dependent way. In a sprouting assay we found that IL-20 caused cell migration within 24 h at a rate comparable to VEGF-C, and this migration could be inhibited by wortmannin and rapamycin. These data show that IL-20 activates cell signalling resulting in lymphangiogenic processes including migration, proliferation and tube formation. Thus, IL-20 is a cytokine that has the potential of activating or modulating the formation of lymphatic vessels.

AB - IL-20 is an arteriogenic cytokine that remodels collateral networks in vivo, and plays a role in cellular organization. Here, we investigate its role in lymphangiogenesis using a lymphatic endothelial cell line, hTERT-HDLEC, which expresses the lymphatic markers LYVE-1 and podoplanin. Upon stimulation of hTERT-HDLEC with IL-20, we found an increase in the intracellular free calcium concentration, in Akt and eNOS phosphorylations as well as in perinuclear NO production. We found that eNOS phosphorylation and NO synthesis are highly dependent on the PI3K/Akt signalling pathway. We also found an IL-20 induced phosphorylation of Erk1/2 and mTOR, and using the MEK inhibitor PD98059 and mTOR complex inhibitor rapamycin we demonstrated the importance of these signalling pathways in IL-20-mediated proliferation. IL-20 triggered actin polymerization and morphological changes resulting in elongated cell structures, and in matrigels, IL-20 caused tube formations of hTERT-HDLEC in a PI3K- and mTOR dependent way. In a sprouting assay we found that IL-20 caused cell migration within 24 h at a rate comparable to VEGF-C, and this migration could be inhibited by wortmannin and rapamycin. These data show that IL-20 activates cell signalling resulting in lymphangiogenic processes including migration, proliferation and tube formation. Thus, IL-20 is a cytokine that has the potential of activating or modulating the formation of lymphatic vessels.

U2 - 10.1016/j.mvr.2009.02.007

DO - 10.1016/j.mvr.2009.02.007

M3 - Journal article

C2 - 19281830

VL - 78

SP - 25

EP - 32

JO - Microvascular Research

JF - Microvascular Research

SN - 0026-2862

IS - 1

ER -