title: Evidence of IL-18 as a novel angiogenic mediator.
abstract: Angiogenesis, or new blood vessel growth, is a key process in the development of synovial inflammation in rheumatoid arthritis (RA). Integral to this pathologic proliferation are proinflammatory cytokines. We hypothesized a role for IL-18 as an angiogenic mediator in RA. We examined the effect of human IL-18 on human microvascular endothelial cell (HMVEC) migration. IL-18 induced HMVEC migration at 1 nM (p < 0.05). RA synovial fluids potently induced endothelial cell migration, but IL-18 immunodepletion resulted in a 68 +/- 5% decrease in HMVEC migration (p < 0.05). IL-18 appears to act on HMVECs via alpha(v)beta(3) integrin. To test whether IL-18 induced endothelial cell tube formation in vitro, we quantitated the degree of tube formation on Matrigel matrix. IL-18, 1 or 10 nM, resulted in a 77% or 87% increase in tube formation compared with control (p < 0.05). To determine whether IL-18 may be angiogenic in vivo, we implanted IL-18 in Matrigel plugs in mice, and IL-18 at 1 and 10 nM induced angiogenesis (p < 0.05). The angiogenesis observed appears to be independent of the contribution of local TNF-alpha, as evidenced by adding neutralizing anti-TNF-alpha Ab to the Matrigel plugs. In an alternative in vivo model, sponges embedded with IL-18 or control were implanted into mice. IL-18 (10 nM) induced a 4-fold increase in angiogenesis vs the control (p < 0.05). These findings support a novel function for IL-18 as an angiogenic factor in RA and may elucidate a potential therapeutic target for angiogenesis-directed diseases.
authors.affiliation: Department of Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Park
authors.forename: J C
authors.initials: JC
authors.lastname: Morel
authors.forename: M A
authors.initials: MA
authors.lastname: Amin
authors.forename: M A
authors.initials: MA
authors.lastname: Connors
authors.forename: L A
authors.initials: LA
authors.lastname: Harlow
authors.forename: A E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D054365:Chemokine CXCL5; D018925:Chemokines / Q000502:physiology; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000502:physiology; D003094:Collagen / Q000008:administration & dosage; D004338:Drug Combinations; D004343:Drug Implants; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development / Q000276:immunology; D006099:Granuloma / Q000503:physiopathology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000502:physiology; D007797:Laminin / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000276:immunology; D011161:Porifera; D011509:Proteoglycans / Q000008:administration & dosage; D019030:Receptors, Vitronectin / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D013582:Synovial Fluid / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004338:Drug Combinations; D004343:Drug Implants; D007106:Immune Sera; D020382:Interleukin-18; D016209:Interleukin-8; D007797:Laminin; D011509:Proteoglycans; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C059485:matrigel; D003094:Collagen