scholarly journals Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation

2003 ◽  
Vol 198 (10) ◽  
pp. 1517-1525 ◽  
Author(s):  
Arihiro Kano ◽  
Michael J. Wolfgang ◽  
Qian Gao ◽  
Joerg Jacoby ◽  
Gui-Xuan Chai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Endotoxic Shock ◽  
Transforming Growth Factor Β ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Protective Function ◽  
Lps Challenge

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

scholarly journals Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

2004 ◽  
Vol 72 (4) ◽  
pp. 1974-1982 ◽  
Author(s):  
M. S. Khalifeh ◽  
J. R. Stabel
Keyword(s):  
Growth Factor ◽  
Cell Cultures ◽  
Mycobacterium Avium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

scholarly journals Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition)

TH Open ◽  
2019 ◽  
Vol 03 (03) ◽  
pp. e230-e243 ◽  
Author(s):  
Virginia Albiñana ◽  
Guillermo Giménez-Gallego ◽  
Angela García-Mato ◽  
Patricia Palacios ◽  
Lucia Recio-Poveda ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Orphan Drug ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Life Threatening ◽  
Vascular Dysplasia ◽  
Pathway Inhibition

AbstractHereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in Endoglin and ACVRL1/ALK1, genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016–003982–24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).

scholarly journals Extracellular Vesicles from Cryptococcus neoformans Modulate Macrophage Functions

2010 ◽  
Vol 78 (4) ◽  
pp. 1601-1609 ◽  
Author(s):  
Débora L. Oliveira ◽  
Célio G. Freire-de-Lima ◽  
Joshua D. Nosanchuk ◽  
Arturo Casadevall ◽  
Marcio L. Rodrigues ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Extracellular Vesicles ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Biologically Active ◽  
Host Cells ◽  
Phagocytic Cells ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans and distantly related fungal species release extracellular vesicles that traverse the cell wall and contain a varied assortment of components, some of which have been associated with virulence. Previous studies have suggested that these extracellular vesicles are produced in vitro and during animal infection, but the role of vesicular secretion during the interaction of fungi with host cells remains unknown. In this report, we demonstrate by fluorescence microscopy that mammalian macrophages can incorporate extracellular vesicles produced by C. neoformans. Incubation of cryptococcal vesicles with murine macrophages resulted in increased levels of extracellular tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), and transforming growth factor β (TGF-β). Vesicle preparations also resulted in a dose-dependent stimulation of nitric oxide production by phagocytes, suggesting that vesicle components stimulate macrophages to produce antimicrobial compounds. Treated macrophages were more effective at killing C. neoformans yeast. Our results indicate that the extracellular vesicles of C. neoformans can stimulate macrophage function, apparently activating these phagocytic cells to enhance their antimicrobial activity. These results establish that cryptococcal vesicles are biologically active.

Effects of folic acid supplement on uterine prostaglandin metabolism and interleukin-2 expression on day 15 of gestation in white breed and crossbred Meishan sows

2004 ◽  
Vol 84 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Frédéric Guay, J. Jacques Matte ◽  
Christiane L. Girard ◽  
Marie-France Palin, Alain Giguère ◽  
Jean-Paul Laforest
Keyword(s):  
Folic Acid ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Interferon Γ ◽  
Prostaglandin E ◽  
Cyclooxygenase 1 ◽  
White Breed ◽  
Uterine Environment

The effects of a dietary folic acid (B9) supplement on the uterine environment of nulliparous Yorkshire- Landrace (YL) and multiparous Landrace (LD) and multiparous Meishan-Landrace (ML) sows were investigated. Sows were randomly assigned to two treatments: 0 mg kg-1 and 15 mg kg-1 of B9. The supplements were given daily from the estrus preceding insemination up to slaughter on Day 15 of gestation. At slaughter, one uterine horn was used to collect the “uterine flush” and conceptuses in order to determine the uterine content of prostaglandin E2(PGE2) and F2α(PGF2α), estradiol-17β (E2) and transforming growth factor-β2 (TGF-β2), and conceptus expression of cytochrome P450aromatase (P450) and interferon γ mRNA (IFNγ). The other horn was used to determine endometrial expression of interleukin-2 (IL-2), cyclooxygenase-1 (COX1) and -2 (COX2) mRNA and to evaluate endometrial in vitro secretion of PGE2. The B9 supplement tended to decrease the uterine content of PGE2 (P < 0.08), and decrease endometrial expression of COX1 mRNA (P < 0.05). The in vitro secretion of PGE2 was reduced by B9 supplement only in YL sows (P < 0.05). The type of sow did not have any effect on the uterine content of PGE2 (P > 0.10). However, endometrial expression of COX2 mRNA was lower for YL than LD sows (P < 0.05), but there was no difference between ML and LD sows. Endometrial expression of COX1 mRNA was higher for ML than LD sows (P < 0.05). The B9 supplement tended to decrease uterine content of E2 and TGF-β2 in YL and LD sows (P < 0.07), but conceptus expression of P450 mRNA increased only for YL sows (P < 0.05). The uterine content of E2 was lower for YL than LD sows (P < 0.05). The B9 supplement decreased endometrial expression of IL-2 mRNA in LD and YL sows ( P < 0.05), but increased it in ML sows (P < 0.05). Conceptus expression of IFNγ mRNA was not affected either by B9 supplementation or the type of sow. In conclusion, the effect of B9 supplementation on the porcine uterine environment at Day 15 of gestation was influenced by sow type (genotype and/or parity). Key words: Sow, gestation, folic acid, prostaglandin, interleukin-2

scholarly journals ALK1 signaling regulates early postnatal lymphatic vessel development

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1654-1661 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Minhong Yan
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Lymphatic Endothelial Cells ◽  
Multiple Organs ◽  
Lymphatic Development

Abstract In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

scholarly journals The Effect of Zearalenone on the Cytokine Environment, Oxidoreductive Balance and Metabolism in Porcine Ileal Peyer’s Patches

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 350
Author(s):  
Kazimierz Obremski ◽  
Wojciech Trybowski ◽  
Paweł Wojtacha ◽  
Magdalena Gajęcka ◽  
Józef Tyburski ◽  
...  
Keyword(s):  
Stress Responses ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Basal Metabolism ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
Factor Α

The aim of the present study was to determine the effect of zearalenone (ZEN), administered per os to gilts at doses equivalent to 50%, 100%, and 150% of no-observed-adverse-effect level (NOAEL) values for 14, 28, and 42 days during weaning, on changes in the parameters of the oxidoreductive balance, cytokine secretion, and basal metabolism in ileal Payer’s patches. Immunoenzymatic ELISA tests and biochemical methods were used to measure the concentrations of interleukin 1α, interleukin 1β, interleukin 12/23p40, interleukin 2, interferon γ, interleukin 4, interleukin 6, interleukin 8, tumor necrosis factor α, interleukin 10, transforming growth factor β, malondialdehyde, sulfhydryl groups, fructose, glucose, and proline, as well as the activity of peroxidase, superoxide dismutase and catalase. The study demonstrated that ZEN doses corresponding to 50%, 100%, and 150% of NOAEL values, i.e., 5 µg, 10 µg, and 15 µg ZEN/kg BW, respectively, have proinflammatory properties, exacerbate oxidative stress responses, and disrupt basal metabolism in ileal Payer’s patches in gilts.

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