Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases.
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.


CONCLUSIONS
Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.
Amin
M Asif
MA
Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. maamin@umich.edu
Rabquer
Bradley J
BJ
Mansfield
Pamela J
PJ
Ruth
Jeffrey H
JH
Marotte
Hubert
H
Haas
Christian S
CS
Reamer
Elyse N
EN
Koch
Alisa E
AE
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000172:deficiency / Q000494:pharmacology* / Q000502:physiology; D007797:Laminin; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans; D012867:Skin / Q000098:blood supply; D013583:Synovial Membrane / Q000473:pathology / Q000637:transplantation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D019061:src-Family Kinases; D048670:MAP Kinase Kinase 4