Interleukin-4 and granulocyte-macrophage colony-stimulating factor mediates the upregulation of soluble vascular endothelial growth factor receptor-1 in RAW264.7 cells—a process in which p38 mitogen-activated protein kinase signaling has an important role

Xia, Lin; Dong, Zhaogang; Zhang, Yun; Zhang, Xiaoying; Song, Xin; Sun, Mingxia; Hu, Yingwei; Liu, Shaohua; Wang, Ketao; Qu, Xun; Fang, Wei

doi:10.1016/j.jmii.2014.06.008

Cited by 7 publications

(7 citation statements)

References 41 publications

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“…This suggests that the M2a polarization condition up-regulates and secretes the soluble VEGF receptor 1 to regulate extracellular VEGF-A levels; a mechanism known to exist for other cell types (88). Concurrent with our study, another group demonstrated that IL-4 was capable of increasing the production of VEGFR-1 from RAW264.7 macrophages consistent with the expression of Vegfr1 in the current study (89). Our study has expanded this definition to demonstrate the divergent pattern of Vegfr1 across macrophage polarization; decreased expression of Vegfr1 and the consistent increase in VEGF-A in the M1 polarization condition.…”

Section: Discussionsupporting

confidence: 90%

“…elicited peritoneal macrophage activation with IL-4 and through ex vivo analysis of gene expression reported Flt1 (aka Vegfr1 ) was highly up-regulated (90). However, increased soluble VEGF receptor 1 has been reported in monocytes/macrophages stimulated with GM-CSF (89, 91). As discussed earlier, GM-CSF was elevated in the media of M1 macrophages but in the present study VEGF-A actually increased in the CM and Vegfr1 was down-regulated in a temporally-dependent manner in M1 macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Temporal phenotypic features distinguish polarized macrophagesin vitro

Melton¹,

McManus²,

Gelfond

et al. 2015

Autoimmunity

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Macrophages are important in vascular inflammation and environmental factors influence macrophage plasticity. Macrophage transitions into pro-inflammatory (M1) or anti-inflammatory (M2) states have been defined predominately by measuring cytokines in culture media (CM). However, temporal relationships between cellular and secreted cytokines have not been established. We measured phenotypic markers and cytokines in cellular and CM of murine bone marrow-derived macrophages at multiple time points following stimulation with IFN-γ+LPS (M1), IL-4 (M2a), or IL-10 (M2c). Cytokines/proteins in M1-polarized macrophages exhibited two distinct temporal patterns; an early (0.5–3 hr), transient increase in cellular cytokines (GM-CSF, KC-GRO, MIP-2, IP-10 and MIP-1β) and a delayed (3–6 hrs) response that was more sustained [IL-3, regulated on activation normal T cell expressed and secreted (RANTES), and tissue inhibitor of metalloproteinases 1 (TIMP-1)]. M2a-related cytokine/cell markers (IGF-1, Fizz1, and Ym1) were progressively (3–24 hrs) increased post-stimulation. Additionally, novel patterns were observed. First, and unexpectedly, cellular pro-inflammatory chemokines, MCP-1 and MCP-3 but not MCP-5, were comparably increased in M1 and M2a macrophages. Second, Vegfr1 mRNA was decreased in M1 and increased in M2a macrophages. Finally, VEGF-A was increased in the CM of M1 cultures and strikingly reduced in M2a coinciding with increased Vegfr1 expression, suggesting decreased VEGF-A in M2a CM was secondary to increased soluble VEGFR1. In conclusion, macrophage cytokine production and marker expression were temporally regulated and relative levels compared across polarizing conditions were highly dependent upon the timing and location (cellular vs. CM) of the sample collection. For most cytokines, cellular production preceded increases in the CM suggesting that cellular regulatory pathways should be studied within 6 hours of stimulation. The divergent polarization-dependent expression of Vegfr1 may be essential to controlling VEGF potentially regulating angiogenesis and inflammatory cell infiltration in the vascular niche. The current study expands the repertoire of cytokines produced by polarized macrophages and provides insights into the dynamic regulation of macrophage polarization and resulting cytokines, proteins, and gene expression that influence vascular inflammation.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Temporal phenotypic features distinguish polarized macrophagesin vitro

Melton¹,

McManus²,

Gelfond

et al. 2015

Autoimmunity

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“…Upregulation of inflammatory factors, including VEGF, IL-1b, IL-6, IL-8, intercellular adhesion molecule-1, and MCP-1, have been shown in vitreous or aqueous humor of patients with DR. 2,5,9,11,13,14 There is a significant amount of overlap in pathways of VEGF and cytokines, with previous studies demonstrating activation of VEGF by inflammatory mediators such as Toll-like receptor 3, IL-6, and MCP-1, 41 upregulation of MCP-1 expression by VEGF-A, 42 induction of VEGF expression by IL-6, 43,44 and upregulation of sVEGFR-1 expression by IL-4 and GM-CSF. 45 Interactions between these key pathways led to endothelial cell damage, increased vascular permeability, and leakage. 2,9 Intraocular cytokine levels have been found to be elevated in patients with DME, [10][11][12]15 some of which also demonstrated a positive correlation between some cytokines and macular volume and thickness as a surrogate of the severity of DME.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema

Lim

Bandala‐Sanchez

Kolic

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To evaluate the effect of intravitreal ranibizumab injections on aqueous concentrations of angiogenic or inflammatory cytokines in patients with diabetic macular edema (DME). METHODS. Thirty eyes of 25 patients with center-involved DME were recruited to the study. All had a central macular thickness (CMT) of >300 lm and best-corrected visual acuity (BCVA) between 28 and 70 logMAR letters (Snellen equivalent 20/320-20/40). At baseline, all eyes had 0.1 mL of aqueous collected before ranibizumab treatment. At week 4, a second ranibizumab injection was administered and at week 8, aqueous sampling was repeated before a third ranibizumab injection. From week 12, all eyes were followed at 4-weekly intervals and the need for ranibizumab treatment was determined by BCVA and CMT measurements. Levels of 32 cytokines were assessed at baseline and at week 8 using a multiplex array assay. RESULTS. Following two consecutive ranibizumab injections, there was a statistically significant reduction in VEGF (P < 0.00001), as well as IL-1b (P ¼ 0.00006), IL-7 (P ¼ 0.00002), IL-8 (P ¼ 0.00023), IL-10 (P < 0.00001), IL-12 (P < 0.00001), IL-17 (P ¼ 0.00024), MCP-1 (P ¼ 0.00023), and TNF-a (P < 0.00001). There was also an upregulation of soluble VEGF receptor-2 (P ¼ 0.00004). A P < 0.0015 was considered significant in this study. CONCLUSIONS. Ranibizumab treatment influences various inflammatory cytokine concentrations in addition to reducing aqueous VEGF concentrations in patients with DME. This may contribute to its therapeutic effect in patients with DME.

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“…Taken together, these data suggest that the role of each sVEGFR1 might be highly dependent on the tissue and/or the cell type. Although extracellular signals that control sVEGFR1 expression are largely unknown, endogenous stimuli, such as growth factors [89,90], cytokines [91], hypoxia [92], and miRNAs [93], have been shown to induce the expression of sVEGFR1-i13. Moreover, a cooperative role between the arginine demethylase and lysine hydroxylase JMJD6 (JuMonJi Domain containing-protein 6) and the splicing factor U2AF65 [94], as well as inhibition of the NOTCH1 signalling pathway [95], have been reported to up-regulate the expression of sVEGFR1-i13.…”

Section: Alternative Splicing Of Vegfr1: From Anti-angiogenic To Pmentioning

confidence: 99%

Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy

Abou-Faycal

Hatat

Gazzéri

et al. 2017

IJMS

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Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation. Alternative splicing of pre-mRNA has recently emerged as an important contributor to cancer development and tumour maintenance. Interestingly, RTKs are alternatively spliced. However, the biological functions of RTK splice variants, as well as the upstream signals that control their expression in tumours, remain to be understood. More importantly, it remains to be determined whether, and how, these splicing events may affect the response of tumour cells to RTK-targeted therapies, and inversely, whether these therapies may impact these splicing events. In this review, we will discuss the role of alternative splicing of RTKs in tumour progression and response to therapies, with a special focus on two major RTKs that control proliferation, survival, and angiogenesis, namely, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-1 (VEGFR1).

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Interleukin-4 and granulocyte-macrophage colony-stimulating factor mediates the upregulation of soluble vascular endothelial growth factor receptor-1 in RAW264.7 cells—a process in which p38 mitogen-activated protein kinase signaling has an important role

Abstract: IL-4 and GM-CSF increased sVEGFR1 levels, but did not significantly effect VEGF expression, and led to the antiangiogenesis properties of monocytes. p38 Mitogen-activated protein kinase signaling has an important role in the process.

Cited by 7 publications

References 41 publications

Temporal phenotypic features distinguish polarized macrophagesin vitro

Temporal phenotypic features distinguish polarized macrophagesin vitro

The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema

Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy

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