Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1

Flister, Michael J.; Wilber, Andrew; Hall, Kelly; Iwata, Caname; Miyazono, Kohei; Nisato, Riccardo E.; Pepper, Michael Sean; Zawieja, David C.; Ran, Sophia

doi:10.1182/blood-2008-12-196840

Cited by 181 publications

(201 citation statements)

References 49 publications

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“…The induction of VEGFR3 under these conditions is at first somewhat paradoxical, as NF-B has also been shown to be a positive regulator of VEGFR3 (15). Since miR-9 directly inhibits NF-B, as demonstrated by our Western blot and luciferase assays, it is possible that miR-9 activates other positive regulators of VEGFR3-mediated lymphangiogenesis, such as the Notch family of proteins or neuropilin (56,68), in the absence of NF-B signaling.…”

Section: Mir-21 and The Mir-17-92 Clustermentioning

confidence: 85%

“…Lymphatic endothelial cells (LECs) at a site of inflammation have been shown to actively participate in and regulate inflammatory processes and host immune responses, thereby emerging as major players in progression and resolution of the inflammatory state (18,19,46,47,50,64). Since inflammation acts as a primary trigger for pathological lymphangiogenesis, a number of proinflammatory cytokines have also been shown to function as prolymphangiogenic factors (15,25,49). However, it remains unclear whether lymphangiogenesis is beneficial or detrimental for the resolution of inflammation (2,18).…”

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confidence: 99%

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MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

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Chakraborty S, Zawieja DC, Davis MJ, Muthuchamy M. MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation. Am J Physiol Cell Physiol 309: C680 -C692, 2015. First published September 9, 2015; doi:10.1152/ajpcell.00122.2015.-The lymphatics have emerged as critical players in the progression and resolution of inflammation. The goal of this study was to identify specific microRNAs (miRNAs) that regulate lymphatic inflammatory processes. Rat mesenteric lymphatic endothelial cells (LECs) were exposed to the proinflammatory cytokine tumor necrosis factor-␣ for 2, 24, and 96 h, and miRNA profiling was carried out by real-time PCR arrays. Our data demonstrate a specific set of miRNAs that are differentially expressed (Ͼ1.8-fold and/or P Ͻ 0.05) in LECs in response to tumor necrosis factor-␣ and are involved in inflammation, angiogenesis, endothelial-mesenchymal transition, and cell proliferation and senescence. We further characterized the expression of miRNA 9 (miR-9) that was induced in LECs and in inflamed rat mesenteric lymphatics. Our results showed that miR-9 overexpression significantly repressed NF-B expression and, thereby, suppressed inflammation but promoted LEC tube formation, as well as expression of the prolymphangiogenic molecules endothelial nitric oxide synthase and VEGF receptor type 3. LEC viability and proliferation and endothelial-mesenchymal transition were also significantly induced by miR-9. This study provides the first evidence of a distinct profile of miRNAs associated with LECs during inflammation. It also identifies the critical dual role of miR-9 in fine-tuning the balance between lymphatic inflammatory and lymphangiogenic pathways.

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Section: Mir-21 and The Mir-17-92 Clustermentioning

confidence: 85%

mentioning

confidence: 99%

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

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“…In addition to Sox18, NF-kb (Flister et al 2010(Flister et al , 2011, TGF-b (Oka et al 2008), interleukin-3 (Groger et al 2004), and VEGF-C (Sivakumar et al 2008) have been shown to regulate Prox1 in endothelial cells, but their roles in lymphatic development need to be established. Moreover, regulators of Prox1 have been reported in other types of cells.…”

Section: Prox1: the Master Regulator For Lymphatic Developmentmentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

117

106

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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“…Inflammatory lymphangiogenesis can be driven by immune cell-released VEGF-C, and inflammatory stimuli promote lymphatic endothelial cell susceptibility to VEGF-C through the upregulation of VEGFR3 and Prox-1 [102]. Tissue necrosis factor α, as well as newly recruited macrophages and granulocytes, can enhance the local expression of VEGF-C within inflamed tissue to promote lymphangiogenesis [103].…”

Section: Chronic Inflammationmentioning

confidence: 99%

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

Lund

Swartz

2010

J Mammary Gland Biol Neoplasia

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Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

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Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1

Cited by 181 publications

References 49 publications

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

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