Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that is chemotactic for lymphocytes and neutrophils, is also angiogenic. Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha. An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity. These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis, tumor growth, and wound repair.
Cells within the synovial tissue may recruit mononuclear phagocytes into the synovial fluid and tissues of arthritic patients. We investigated the production of the chemotactic cytokine monocyte chemoattractant protein-i (MCP-1) using sera, synovial fluid, synovial tissue, as well as macrophages and fibroblasts isolated from synovial tissues from 80 arthritic patients. MCP-1 levels were significantly higher (P < 0.05) in synovial fluid from RA patients (mean 25.5±8.1 ng/ml ISEI) compared to synovial fluid from osteoarthritis (OA) patients (0.92±0.08), or from patients with other arthritides (2.9±1.5). MCP-1 levels in RA sera (8.44±2.33) were significantly greater than MCP-1 in normal sera (0.16±0.06). The quantities ofRA synovial fluid IL-8, which is chemotactic for neutrophils and lymphocytes, and MCP-1 were strongly positively correlated (P < 0.05). To examine the cellular source of MCP-1, RA synovial tissue macrophages and fibroblasts were isolated. Synovial tissue fibroblasts did not express MCP-1 mRNA, but could be induced to produce MCP-1 by stimulation with either IL-1#, tumor necrosis factor-alpha (TNF-a), or LPS. In contrast, unlike normal peripheral blood monocytes or alveolar macrophages, RA synovial tissue macrophages constitutively expressed MCP-1 mRNA and antigen. Immunohistochemical analysis of synovial tissue showed that a significantly greater percentage of RA macrophages (50±8%) as compared to either OA macrophages (5±2) or normal macrophages (1±0.3) reacted with anti-MCP-1 antibodies. In addition, the synovial lining layer reacted with MCP-1 in both RA and OA synovial tissues. In contrast, only a minority of synovial fibroblasts (18±8%) from RA synovium were positive for immunolocalization of MCP-1. These results suggest that synovial production of MCP-1 may play an important role in the recruitment of mononuclear phagocytes during inflammation associated with RA and that synovial tissue macrophages are the dominant source of this cytokine. (J. Clin. Invest. 1992. 90:772-779.)
We have shown that human macrophages (m4s) play an important role in the elaboration of chemotactic cytokines in rheumatoid arthritis (RA) (Koch, inflammatory protein-i (MIP-la), a cytokine with chemotactic activity for mos and neutrophils (PMNs), has been described. We have examined the production of MIP-1a using sera, synovial fluid (SF), and synovial tissue (ST) from 63 arthritic patients. MIP-la was higher in RA SF (mean, 29±8 ng/ml ISEJ) compared with other forms of arthritis (2.8±1.7), or osteoarthritis (0.7±0.4; P < 0.05). RA SF MIP-la was greater than that found in either RA or normal peripheral blood (PB) (P < 0.05). Anti-MIP-la neutralized 36±3% (mean±SE) of the chemotactic activity for mos, but not PMNs, found in RA SFs. RA SF and PB mononuclear cells produced antigenic MIP-la. Mononuclear cell MIP-la production was augmented with phytohemagglutinin or LPS. Isolated RA ST fibroblast production of antigenic MIP-la was augmented upon incubation of cells with LPS, and to a lesser extent with tumor necrosis factor-a. Isolated RA ST m4s expressed constitutive MIP-la mRNA and antigenic MIP-la.AUsing ST immunohistochemistry, MIP-la+ cells from RA compared with normal were predominantly mos and lining cells (P < 0.05). These results suggest that MIP-la plays a role in the selective recruitment of mos in synovial inflammation associated with RA. (J. Clin. Invest. 1994. 93:921-928.)
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 αvβ3 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-α, as evidenced by adding neutralizing anti-TNF-α 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.
Abstract-In this study, we investigated the effects of migration inhibitory factor (rhMIF) on angiogenesis-related signaling cascades and apoptosis in human endothelial cells (ECs). We show that in vitro rhMIF induces migration and tube formation in Matrigel of human dermal microvascular endothelial cells (HMVECs), with potency comparable to that of basic fibroblast growth factor. In vivo, rhMIF induces angiogenesis in Matrigel plugs and in the corneal bioassay. Using panels of relatively specific kinase inhibitors, antisense oligonucleotides, and dominant-negative mutants, we show that mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) are critical for MIF-dependent HMVEC migration, whereas Src and p38 kinases are nonessential. Moreover, we demonstrate that rhMIF induces time-dependent increases in phosphorylation levels of MEK1/2, Erk1/2, and Elk-1, as well as PI3K, and its effector kinase, Akt, in HMVECs. Studies with dominant-negative mutants and antisense oligonucleotides corroborate these effects in HMVECs. Furthermore, we demonstrate that rhMIF-induced angiogenesis in the rat cornea in vivo and in the ex vivo endothelial cell morphogenesis assay is also MAPK-and PI3K-dependent. Our findings support a role for MIF as an angiogenic factor and provide a rationale for the use of MIF as a therapeutic inducer of neovascularization in the development of collateral circulation in coronary artery disease. Angiogenesis is a hallmark of diverse pathological conditions such as rheumatoid arthritis. 3 Angiogenesis is triggered by a number of mediators and chemokines including interleukin (IL)-8. 4 MIF is required for tumor-initiated endothelial cell proliferation and tumor neovascularization: anti-MIF inhibits tumor growth and tumor-associated angiogenesis. 5,6 MIF is found in human vascular endothelial cells (ECs), which are thought to play a pivotal role in systemic inflammatory and immune disorders by producing cytokines and growth factors. 7 Although the critical role of angiogenesis in these disorders has been demonstrated, the signaling cascades that mediate the angiogenic effects of most growth factors and cytokines are not fully understood.Phosphatidylinositol 3-kinase (PI3K) and its downstream target, the serine-threonine kinase, Akt, are implicated in a number of cellular functions such as cell adhesion, cell survival, and angiogenesis. 8,9 MEK1 and MEK2, the activators of MAP or Erk kinases, are dual-specificity proteins that form part of the mitogen-activated protein kinase (MAPK) signaling pathway controlling cell growth and differentiation. 10 We investigated the mechanism by which MIF induces angiogenesis and its protective role against EC apoptosis. We found that MIF is a chemoattractant for ECs and its chemotactic effect is comparable to that of a potent inducer of angiogenesis, basic fibroblast growth factor (bFGF). MIF induces EC morphogenesis in Matrigel in vitro and angiogenesis in vivo, both in the Matrigel plug and corneal angiogenesis assay. MIF-induced chemotaxis ...
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