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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inducing Agents / antagonists & inhibitors
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Angiogenesis Inducing Agents / immunology
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Angiogenesis Inducing Agents / physiology*
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Animals
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / pathology
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Cell Division / immunology
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Cell Line
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Cell Migration Inhibition
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Cell Movement / immunology
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Chemokine CXCL5
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Chemokines / physiology
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Chemokines, CXC*
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Chemotactic Factors / physiology
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Collagen / administration & dosage
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Drug Combinations
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Drug Implants
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Endothelium, Vascular / cytology
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Endothelium, Vascular / growth & development
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Endothelium, Vascular / immunology
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Granuloma / physiopathology
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Humans
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Immune Sera / pharmacology
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Interleukin-18 / administration & dosage
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Interleukin-18 / antagonists & inhibitors
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Interleukin-18 / immunology
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Interleukin-18 / physiology*
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Interleukin-8 / analogs & derivatives
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Interleukin-8 / physiology
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Laminin / administration & dosage
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Mice
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Mice, Inbred C57BL
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Neovascularization, Physiologic / immunology
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Porifera
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Proteoglycans / administration & dosage
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Receptors, Vitronectin / physiology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / immunology
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Recombinant Proteins / pharmacology
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Synovial Fluid / immunology
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Tumor Necrosis Factor-alpha / physiology
Substances
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Angiogenesis Inducing Agents
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CXCL5 protein, human
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Chemokine CXCL5
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Chemokines
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Chemokines, CXC
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Chemotactic Factors
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Drug Combinations
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Drug Implants
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Immune Sera
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Interleukin-18
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Interleukin-8
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Laminin
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Proteoglycans
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Receptors, Vitronectin
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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matrigel
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Collagen