PT  - JOURNAL ARTICLE
AU  - M Asif Amin
AU  - Bradley J Rabquer
AU  - Pamela J Mansfield
AU  - Jeffrey H Ruth
AU  - Hubert Marotte
AU  - Christian S Haas
AU  - Elyse N Reamer
AU  - Alisa E Koch
TI  - Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases
AID  - 10.1136/ard.2009.127241
DP  - 2010 Dec 01
TA  - Annals of the Rheumatic Diseases
PG  - 2204--2212
VI  - 69
IP  - 12
4099  - http://ard.bmj.com/content/69/12/2204.short
4100  - http://ard.bmj.com/content/69/12/2204.full
SO  - Ann Rheum Dis2010 Dec 01; 69
AB  - 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.