title: 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.
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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jagielska
authors.forename: Piyushkumar R
authors.initials: PR
authors.lastname: Kapopara
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Harald
authors.initials: H
authors.lastname: Schütt
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D002465:Cell Movement; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D007375:Interleukin-1; D048051:p38 Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2