Inhibitory effect of human recombinant interleukin-1 α and β on growth of human vascular endothelial cells

Norioka, Kenichi; Hara, Masako; Kitani, Atushi; Hirose, Tatsuo; Hirose, Wataru; Harigai, Masayoshi; Suzuki, Kunihiro; Kawakami, Makoto; Tabata, Hidenori; Kawagoe, Mikio; Nakamura, Haruo

doi:10.1016/0006-291x(87)91060-6

Cited by 49 publications

(16 citation statements)

References 17 publications

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“…1 C and D), suggesting arrest in G1, as also occurs in endothelial cultures treated with transforming growth factor type p3 (15). These findings are consistent with those reported by Norioka et al (24), in which, however, IL-1 effects on endothelial cell growth required higher concentrations of cytokine.…”

Section: Resultssupporting

confidence: 83%

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

Cozzolino

Torcia

Aldinucci

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

173

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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 ...

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Section: Resultssupporting

confidence: 83%

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

Cozzolino

Torcia

Aldinucci

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

173

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“…The result of our study is consistent with the hypothesis that IL-1α limits the growth of bladder tumours. There are several possible, and feasibly additive, mechanisms for anti-tumoral effects by IL-1α, including inhibition of tumour cell growth (Onozaki et al, 1985), anti-angiogenic activities (Norioka et al, 1987) and upregulation of the immunological response (Dinarello, 1996). In experimental systems, forced expression of IL-1α leads to decreased tumorogenicity, and is believed to exert adjuvant-like effects increasing the immunogenicity of tumour-cell antigens (Douvdevani, 1992;Voronov et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…IL-1 has growth inhibitory and cytocidal effects on tumour cell lines (Onozaki et al, 1985). IL-1 upregulates host defences and functions as an immunostimulatory agent (Dinarello, 1996) and has also been reported to have anti-angiogenic activities (Norioka et al, 1987). IL-1 shows some antitumoral activity in melanoma and osteosarcoma patients (Janik et al, 1996) and has been used in clinical trial (Worth et al, 1997).…”

mentioning

confidence: 99%

Low interleukin-1α messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma

Seddighzadeh

Steineck²,

Jansson

et al. 2001

Br J Cancer

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Summary Due to our inability to exactly characterize tumours, many patients with urinary bladder cancer undergo unnecessary surgery or cytostatic therapy. We have here studied the expression of the cytokine interleukin-1α (IL-1α ) in 73 human bladder carcinomas in relation to patient survival, and examined possible relationships between IL-1α and urokinase plasminogen activator (uPA) expression. Expression levels of IL-1α and uPA mRNA were determined by RT-PCR using the quantitative TaqMan technique. The levels of IL-1α mRNA expression did not differ significantly between tumours of different grade or stage. Calculation of the overall survival rates showed a decreased overall survival time for patients with low levels of IL-1α mRNA in their tumours (log rank; P = 0.0002, median follow up: 37 months). Low tumoral IL-1α expression predicted decreased survival of patients with poorly differentiated tumours (P < 0.005) and of patients with invasive tumours (P = 0.02). uPA expression was about 4-fold increased in poorly differentiated tumours. High levels of uPA mRNA were associated with decreased overall survival times (log rank; P = 0.032, n = 60). We conclude that IL-1α is important for bladder cancer biology, and that measurements of this cytokine may be useful in pre-treatment characterization of urinary bladder cancer.

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“…Because IL-la represses the ability of FGF-l to function as an endothelial cell growth factor (14) and IL-la does not contain a signal sequence for secretion (8), we questioned whether IL-la can function as an intracellular repressor of FGF-1-induced cell proliferation in HUVEC populations in vitro. Indeed, treatment of a HUVEC population with an IL-la antisense oligonucleotide delayed the onset of senescence in vitro (13).…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional regulation of interleukin 1 alphain various strains of young and senescent human umbilical vein endothelialcells.

Garfinkel

Brown

Wessendorf

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Human umbilical vein endothelial cell (HU-VEC) senescence in vitro is characterized by the loss of proliferative potential and an increase in cell size. Because HUVEC senescence in one strain (HlOl) has been characterized by the increase in the steady-state mRNA level for the signal-peptideless cytokine, interleukin (IL) la, we have examined young and senescent populations of five additional HUVEC strains (13605, H103, H928, H929, and H930) to determine whether the elevated levels of IL-la mRNA could be observed in all HUVEC strains. Consistent with the data from strain H101, strains H3605 and 1930 also exhibited a low steady-state level of the IL-la mRNA in young populations compared to elevated levels of IL-la mRNA in the senescent populations. However, three strains (H103, H928, and H929) did not exhibit reduced levels of IL-la mRNA in the young populations, and interestingly, strain H928, at times, expressed relatively high IL-la mRNA levels in the young populations. In addition, expression of the steady-state level of plainogen activator inhibitor 1 and cyclooxygenase 2 was elevated in senescent populations of all HUVEC strains examined, whereas young populations exhibited a low level of expression for these genes regardless of the IL-la mRNA level. Further, the level of the IL-la polypeptide was elevated in senescent HUVEC populations relative to young populations that expressed either a high or low level of the IL-la mRNA. We have also demonstrated that the elevated level of IL-la mRNA in the senescent population of strain H3605 may be regulated by mRNA stability; however, this mechanism does not apply to all the HUVEC strains examined in this study. Thus, we suggest that while mRNA levels of the IL-1-response genes for plasminogen activator inhibitor 1 and cyclooxygenase 2 are appropriate markers for HUVEC senescence, HUVEC strain-specific post-transcriptional mechanisms may exist to regulate the function of IL-la as a modifier of HUVEC senescence in vitro.

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Inhibitory effect of human recombinant interleukin-1 α and β on growth of human vascular endothelial cells

Cited by 49 publications

References 17 publications

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

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

Low interleukin-1α messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma

Post-transcriptional regulation of interleukin 1 alphain various strains of young and senescent human umbilical vein endothelialcells.

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