Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases.
Ann Rheum Dis
; 69(12): 2204-12, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-20679476
ABSTRACT
BACKGROUND:
Interleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA).OBJECTIVE:
To examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved.METHODS:
Human dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice.RESULTS:
IL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1α did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo.CONCLUSION:
Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
Endotélio Vascular
/
Quinases da Família src
/
Interleucina-18
/
Indutores da Angiogênese
/
MAP Quinase Quinase 4
/
Neovascularização Patológica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Ann Rheum Dis
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos