Interleukin-1β 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

Abstract

Objective-: Interleukin-1β (IL-1β) is a major cytokine linking inflammation and angiogenesis in pathological vascular processes, such as atherosclerosis and tumor neoangiogenesis. However, signaling pathways mediating IL-1β-induced proangiogenic processes in endothelial cells (ECs) have barely been elucidated yet. Therefore, the present study investigated IL-1β-induced proangiogenic signaling in ECs. Methods And Results-: IL-1β 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-1β-induced processes. Moreover, IL-1β 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-1β-induced activation of p38-MAPK and MK2, as well as IL-1β-induced tube formation and migration. Finally, silencing of TRAF6 and MK2 deficiency inhibited IL-1β-induced microvessel outgrowth in murine aortic rings ex vivo, and deficiency of MK2 or caveolin-1 significantly reduced IL-1β-induced angiogenesis in mice in vivo (Matrigel plug assay). Conclusion-: IL-1β 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. © 2012 American Heart Association, Inc.