Interleukin 1 is an autocrine regulator of human endothelial cell growth.

Abstract

Proliferation of endothelial cells is regulated through the autocrine production of growth factors and the expression of cognate surface receptors. In this study, we demonstrate that interleukin 1 (IL-1) is an inhibitor of endothelial growth in vitro and in vivo. IL-1 arrested growing, cultured endothelial cells in GI phase; inhibition of proliferation was dose dependent and occurred in parallel with occupancy of endothelial surface IL-1 receptors. In an angiogenesis model, IL-1 could inhibit fibroblast growth factor-induced vessel formation. The autocrine nature of the IL-1 effect on endothelial proliferation was demonstrated by the observation that occupancy of cell-surface receptors by endogenous IL-1 depressed cell growth. The potential significance of this finding was emphasized by the detection of IL-1 in the native endothelium of human umbilical veins. A mechanism by which IL-1 may exert its inhibitory effect on endothelial cell growth was suggested by studies showing that IL-1 decreased the expression of high-affinity fibroblast growth factor binding sites on endothelium. These results point to a potentially important role of IL-1 in regulating blood vessel growth and suggest that autocrine production of inhibitory factors may be a mechanism controlling proliferation of normal cells.Control of normal cell proliferation involves the interaction of factors both promoting and inhibiting cell growth (reviewed in ref. 1). In general, it is believed that such substances are conveyed from the extracellular environment; however, certain cell types, such as T lymphocytes or endothelial cells, have been shown to produce growth factors in an autocrine manner. In fact, secretion of interleukin (IL)-2 and IL-4 is a central event in T-cell proliferation, and regulated endogenous production of angiogenic factors promotes development of microvessels (2-4). It is known that T cells maintain tight control over this potentially explosive condition, at least in part by regulating the expression of growth factor receptors (5-7). An additional mechanism would include the production of growth inhibitors. These observations led us to consider that in endothelium, which constitutively produces a potent angiogenic agent, fibroblast growth factor (FGF), control of proliferation could occur through endogenous production of an inhibitor, which could act by controlling expression of the FGF receptor.IL-1, a central mediator of the host response, is made by many cell types, including endothelium (8, 9). This cytokine induces changes in endothelial physiology, enabling these cells to participate actively in immune and inflammatory reactions (10-12). In several systems, IL-1 also acts as a growth-promoting substance, in addition to regulating synthesis ofand responsiveness to other cytokines. In this study, we demonstrate that IL-1, a product of endothelial cells, interacts in an autocrine manner with high-affinity cellsurface receptors to inhibit endothelial growth. The mechanism of IL-1-induced suppression of endothelial cell ...

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

“…Similarly, IL-1, acting via cyclooxygenase 2 (45,46) and nitric oxide (36), also mediates the expression of bFGF. Notwithstanding a conflicting report that IL-1 can inhibit bFGF-induced angiogenesis in a rabbit corneal angiogenesis model (47), the preponderance of evidence, including the data acquired in our corneal angiogenesis model, suggests that IL-1 plays some part in vivo in the induction of angiogenesis by bFGF and VEGF. More important, our findings clearly show that inhibition of IL-1 suppresses angiogenesis in arthritic joints.…”

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells

“…However, VPF/VEGF is known to induce PAI-1 expression in microvascular endothelial cells (Pepper et al, 1991). Furthermore, IL-1a is thought to inhibit cell proliferation by blocking the e ects of growth factors (Cozzolino et al, 1990). Taken together, it is unlikely that VPF/VEGF blocks senescence in HDMEC by regulating endogenous IL-1a levels.…”

Charakterisierung molekularer Mechanismen der anti-angiogenen Aktivität von GBP-1 in Endothelzellen

“…2A) (Cramer and Johnson, 2003;Plate et al, 1992;Shweiki et al, 1992 (Carmeliet, 2005;Veikkola et al, 2000) Thrombospondin (Rodriguez-Manzaneque et al, 2001) basischer Fibroblastenwachstumsfaktor (bFGF) (Dow and deVere White, 2000) Angiostatin (O'Reilly et al, 1994) platelet-derived growth factor (PDGF) (Ostman, 2004) Interferon (IFN)-γ γ γ γ (Friesel et al, 1987) Angiopoietin (Ang)-1 und Tyrosinkinaserezeptor (Tie)-2 (Koblizek et al, 1998) Interleukin (IL)-1 (Cozzolino et al, 1990) Integrin α α α α v β β β β 3 und Integrin α α α α 5 β β β β 1 (Brooks et al, 1994a) Tumornekrosefaktor (TNF)-α α α α (Schweigerer et al, 1987) Angiopoietin (Ang)-1 spielen neben VEGF bei der Angiogenese eine bedeutende Rolle (Koblizek et al, 1998 (Carmeliet and Jain, 2000).…”

“…Des Weiteren wurde sowohl für IL-1, als auch für TNF-α eine antiangiogene Wirkung nachgewiesen. Beide Zytokine lösen einen Zellzyklusarrest in der G1-Phase des Zellzyklus aus, wodurch die Proliferation der EZ gehemmt wird (Cozzolino et al, 1990;Guenzi et al, 2001). Die meisten der durch IL-1-und TNF-α-induzierten Funktionen werden durch den…”

“…Von allen diesen Zytokinen ist bekannt, dass sie antiangiogen wirken, da sie die Proliferation von EZ hemmen (siehe Tab. 1 und Abschnitt 2.3) (Cozzolino et al, 1990;Frater-Schroder et al, 1987;Friesel et al, 1987;Schweigerer et al, 1987 . Im Gegensatz dazu ist für die Induktion der GBP-1-Expression nach einer Behandlung mit IL-1β und TNF-α neben der Aktivierung von IRF-1 die Beteiligung eines weiteren Transkriptionsfaktors notwendig.…”