IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis

Zhang, Qiuhua; Jiang, Youde; Miller, Matthew J.; Peng, Bonnie; Liu, Li; Soderland, Carl; Tang, Jie; Kern, Timothy S.; Pintar, John E.; Steinle, Jena J.

doi:10.1167/iovs.13-12497

Cited by 34 publications

(43 citation statements)

References 25 publications

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“…Thus, our data strongly supports work in other organs that TLR4 can reduce insulin signaling. These data agree with other studies on IGFBP-3 and β-adrenergic receptors, which showed altered insulin signaling, despite normal glucose levels [24, 25]. Further studies on insulin signal transduction and TLR4 will be done once these mice are made diabetic.…”

Section: 0 Discussionsupporting

confidence: 91%

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

et al. 2017

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Objective and Design Work in multiple organs has suggested that toll-like receptor 4 (TLR4) may play a role in insulin resistance. Additional studies have shown a negative role for TLR4 on retinal health. We have previously reported that β-adrenergic receptors can regulate both TLR4 signal transduction, as well as insulin signaling in the retina and in retinal endothelial cells (REC). Thus, we hypothesized that TLR4 would regulate retinal insulin signaling. Materials and Methods We used endothelial cell specific TLR4 knockout mice, as well as TLR4 overexpressing mice for these studies. Methods Western blotting and ELISA analyses were done for investigations of insulin receptor, insulin receptor substrate 1 (IRS-1) serine 307, and Akt phosphorylation, as well as cleaved caspase 3 levels in the mouse retina. Results We found that loss of TLR4 led to increased insulin receptor and Akt phosphorylation, as well as decreased IRS-1Ser307 levels. In support of these results, TLR4 overexpression decreased insulin signaling and the cleavage of caspase 3. Conclusions Therefore, these results suggest that TLR4 plays a key role in insulin signaling in the retina. Reduction of TLR4 levels may be protective to the retina.

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Section: 0 Discussionsupporting

confidence: 91%

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

et al. 2017

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“…It was postulated that this anti-inflammatory effect may be protective in the setting of diabetic nephropathy, which is supported by a study showing that TNFA, which is proinflammatory, reduced IGFBP3 expression in retinal endothelial cells via activation of p38a MAPK and casein kinase 2 under high glucose conditions . Furthermore, IGFBP3 inhibited whereas TNFA increased retinal endothelial cell apoptosis (Zhang et al 2013c). …”

Section: Diabetic Retinopathymentioning

confidence: 99%

Endothelial cells and the IGF system

Bach¹

2014

Journal of Molecular Endocrinology

153

118

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Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.

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“…However, two other members of the IGFBP family are known to be associated with cytokine production, namely IGFBP3 and IGFBP5. The loss of IGFBP3 was previously shown to be associated with an increase in TNF-α expression, 30 and Ad.IGFBP-3 was found to down-regulate both local and systemic levels of NF-κB-targeted proinflammatory cytokines. 31 Moreover, Lee et al reported that IGFBP3 degrades NF-κB regulatory molecules (IκBα and p65-NF-κB), thereby demonstrating that IGFBP-3R can mediate caspase activation via an IGF-independent mechanism.…”

Section: Discussionmentioning

confidence: 89%

“…28 IGFBP3 and IGFBP5 were already known to suppress the secretion of proinflammatory cytokines by inhibiting the NF-κB signaling pathway. [29][30][31][32] Therefore, we studied whether this signaling pathway is involved in the IGFBP7-mediated suppression of cytokines. After T-cells were cocultured with MSC con , their protein levels of p-p65 and p-IκBα in CD3-T-cells were significantly down-regulated.…”

Section: Igfbp7 Knockdown In Mscs Restores the Proinflammatory Cytokimentioning

confidence: 99%

Mesenchymal Stromal Cells Mitigate Experimental Colitis via Insulin-like Growth Factor Binding Protein 7-mediated Immunosuppression

et al. 2016

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Mesenchymal stromal cells (MSCs) have shown great potential for treating inflammatory bowel disease, which is ameliorated through paracrine cross talk between MSCs and T-cells. Members of the insulin-like growth factor binding protein (IGFBP) family have important immunomodulatory functions in MSCs, but the underlying mechanisms behind these functions have not yet been clearly elucidated. In this study, we investigate whether MSC-produced IGFBP7 is involved in immune modulation using a mouse experimental colitis model. Gene expression profiling revealed that IGFBP7 was highly expressed in MSCs. Consistent with this findings, IGFBP7 knockdown in MSCs significantly decreased their immunomodulatory properties, decreasing the antiproliferative functions of MSCs against T-cells, while also having an effect on the proinflammatory cytokine production of the T-cells. Furthermore, in the mouse experimental colitis model, MSC-derived IGFBP7 ameliorated the clinical and histopathological severity of induced colonic inflammation and also restored the injured gastrointestinal mucosal tissues. In conclusion, IGFBP7 contributes significantly to MSC-mediated immune modulation, as is shown by the ability of IGFBP7 knockdown in MSCs to restore proliferation and cytokine production in T-cells. These results suggest that IGFBP7 may act as a novel MSC-secreted immunomodulatory factor.

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IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis

Abstract: Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.

Cited by 34 publications

References 25 publications

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

Endothelial cells and the IGF system

Mesenchymal Stromal Cells Mitigate Experimental Colitis via Insulin-like Growth Factor Binding Protein 7-mediated Immunosuppression

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