Effects of Interferon‐Γ on Secretion of Vascular Endothelial Growth Factor by Endometrial Stromal Cells

Kawano, Yasushi; Matsui, Noriko; Kamihigashi, Shouko; Narahara, Hisashi; Miyakawa, Isao

doi:10.1111/j.8755-8920.2000.430109.x

Cited by 34 publications

(28 citation statements)

References 23 publications

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“…These cytokines do not increase VEGF expression in stromal cultures (M. L. IruelaArispe, unpublished observations), 17 in fact, one study reported a decrease in VEGF transcripts after 6 hours of stromal cell exposure to IFN-␥. 44 In our endometrial stromal cultures, the positive contributions of estradiol and progesterone to VEGF upregulation were modest, with maximal 1.6-to 1.8-fold increases, as has been reported by others. 13,28,29,45 Although VEGF up-regulation in the secretory phase may be explained by progesterone effects, it is unlikely sex steroids play a direct role on VEGF regulation during postmenstrual repair as circulating estrogen and progesterone levels are physiologically low at this point in the cycle.…”

Section: Discussionsupporting

confidence: 80%

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

Graubert

Ortega

Kessel

et al. 2001

The American Journal of Pathology

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Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-␣, and interleukin-1␤. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation The cyclic regeneration of the endometrium during the female reproductive years requires a highly regulated angiogenic response.1-5 Physiological changes associated with loss and reconstruction of the functional endometrium during the menstrual cycle are unique to the higher primate species. Humans undergo shedding of the upper spongy layer of the endometrium during menses. 4,6,7 Menstrual bleeding itself is brought on by tissue breakdown and damage surrounding superficial endometrial vessels. Within 5 days of menstrual onset, the damaged endometrial vessels have been repaired. 8 Hence, the initial phase of endometrial angiogenesis involves repair of the vascular bed in concert with the late stages of menstrual shedding and during the proliferative phase. Models of endometrial angiogenesis in the proliferative phase describe the growth of the vasculature under the influence of estrogen, whereas the secretory phase involves growth of the coiled arterioles mediated by progesterone.

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Section: Discussionsupporting

confidence: 80%

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

Graubert

Ortega

Kessel

et al. 2001

The American Journal of Pathology

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“…Although it was reported that IFN-g itself could inhibit VEGF expression by endometrial stromal cells 20 and has direct antiproliferative effects on some tumor cell lines, 19 in our animal models, immunization of mice with such dose of DC-IFN-g did not show any significant inhibitory effects on tumor cell-induced angiogenesis and metastasis, suggesting that the enhanced antimetastatic effect of DC-sflk1-IFN-g vaccination was not the direct result of growth inhibition of tumor cells by IFN-g secreted by DC-sflk1-IFN-g. Furthermore, our in vivo T-cell subset depletion experiment showed that the antimetastatic effect induced by DC-sflk1 or DC-sflk1-IFN-g vaccination was CD8…”

Section: Antiangiogenic Cancer Immunotherapy With Gene-modified DC J mentioning

confidence: 97%

“…20 These results make IFN-g an attractive cytokine for DC-based antiangiogenic immunotherapy of cancer.…”

Section: Introductionmentioning

confidence: 99%

Enhanced antimetastatic effect of fetal liver kinase 1 extracellular domain and interferon-gamma fusion gene-modified dendritic cell vaccination

et al. 2005

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Antiangiogenic immunotherapy benefits from targeting antigens expressed on genetically stable endothelial cells and represents a novel modality for cancer treatment. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2, also known as flk1 in mouse) mediated VEGF signaling is the key rate-limiting step in angiogenesis. Blockade of the flk1 signaling pathway can significantly inhibit tumor cell-induced angiogenesis and lead to inhibition of tumor metastasis. Interferon-gamma (IFN-g) is a pleiotropic cytokine, which plays an important role in cell-mediated immunity. In this study, we tested the hypothesis that immunization of mice with soluble flk1 (sflk1) and IFN-g fusion gene-transfected dendritic cells (DC-sflk1-IFN-g) would induce a potent CTL response to flk1, leading to an inhibition of tumor-induced angiogenesis and metastasis. Our data show that immunization of mice with sflk1 gene-modified DC (DC-sflk1) could induce a CTL response to flk1, leading to profound inhibition of tumor-cell-induced angiogenesis and metastasis. However, more striking antimetastatic effects were achieved through induction of enhanced CTL response to flk1 and augmented inhibition of angiogenesis when mice were immunized with DC-sflk1-IFN-g. In vivo T-cell subset depletion experiments showed that CD8 + T cells were mainly responsible for this antimetastatic effect. Our data extend the notion that DC-based active antiangiogenic immunotherapy is an effective modality for cancer treatment, and show that the antitumor efficacy of this strategy can be improved by combination with DC-based cytokine immunotherapy. Gene Therapy (2005) 12, 742-750.

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“…IFN-γ is classically considered as a pro-inflammatory factor, yet in recent years, multiple studies have found IFN-γ to mediate an immune-modulatory and protective function. For example, in human endothelial cells IFN-γ inhibits the angiogenic activity of VEGF through activation of STAT1 pathway [48], down-regulating VEGF mRNA in a dosage-dependent manner [49]. This may help to inhibit excess angiogenesis process in wet AMD.…”

Section: Is There Any Beneficial Role Of Ifn-γ In Terms Of Protectivementioning

confidence: 99%

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Jiang¹,

Cao²

2012

J Clin Exp Ophthalmol

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Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating antiinflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.

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Effects of Interferon‐Γ on Secretion of Vascular Endothelial Growth Factor by Endometrial Stromal Cells

Abstract: ES cells produce VEGF, which may contribute to endometrial neovascularization and proliferation. IFN-gamma may play an important role in regulating VEGF production by ES cells.

Cited by 34 publications

References 23 publications

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

Enhanced antimetastatic effect of fetal liver kinase 1 extracellular domain and interferon-gamma fusion gene-modified dendritic cell vaccination

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

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