| First Author | Jagielska J | Year | 2012 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 32 |
| Issue | 5 | Pages | 1280-8 |
| PubMed ID | 22345171 | Mgi Jnum | J:196935 |
| Mgi Id | MGI:5490212 | Doi | 10.1161/ATVBAHA.111.243477 |
| Citation | Jagielska J, et al. (2012) Interleukin-1 assembles a proangiogenic signaling module consisting of caveolin-1, tumor necrosis factor receptor-associated factor 6, p38-mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 in endothelial cells. Arterioscler Thromb Vasc Biol 32(5):1280-8 |
| abstractText | OBJECTIVE: Interleukin-1beta (IL-1beta) is a major cytokine linking inflammation and angiogenesis in pathological vascular processes, such as atherosclerosis and tumor neoangiogenesis. However, signaling pathways mediating IL-1beta-induced proangiogenic processes in endothelial cells (ECs) have barely been elucidated yet. Therefore, the present study investigated IL-1beta-induced proangiogenic signaling in ECs. METHODS AND RESULTS: IL-1beta potently induced tube formation and migration of ECs. This was associated with and dependent on activation of p38-mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) as determined by pharmacological inhibition and gene silencing. Furthermore, silencing of the adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) (lentiviral short hairpin RNA) inhibited these IL-1beta-induced processes. Moreover, IL-1beta promoted translocation of TRAF6 to insoluble cellular fractions (containing membrane rafts/caveolae) and interaction of TRAF6 with caveolin-1. Accordingly, cellular cholesterol depletion (cyclodextrin) and silencing of caveolin-1 (small interfering RNA) inhibited IL-1beta-induced activation of p38-MAPK and MK2, as well as IL-1beta-induced tube formation and migration. Finally, silencing of TRAF6 and MK2 deficiency inhibited IL-1beta-induced microvessel outgrowth in murine aortic rings ex vivo, and deficiency of MK2 or caveolin-1 significantly reduced IL-1beta-induced angiogenesis in mice in vivo (Matrigel plug assay). CONCLUSIONS: IL-1beta assembles a proangiogenic signaling module consisting of caveolin-1, TRAF6, p38-MAPK, and MK2 in ECs, representing a potential target to intervene into angiogenesis-dependent processes and diseases. |
