scholarly journals Interleukin-33 stimulates stress in the endoplasmic reticulum of the human myometrium via an influx of calcium during initiation of labor

2021 ◽  
Author(s):  
Li Chen ◽  
Zhenzhen Song ◽  
Xiaowan Cao ◽  
Mingsong Fan ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Er Stress ◽  
Muscle Cells ◽  
Human Myometrium ◽  
Premature Delivery ◽  
Interleukin 33 ◽  
Uterine Smooth Muscle ◽  
Cox 2

Background: Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the IL-1β family, interleukin-33 (IL-33) has been shown to be involved in a variety of pregnancy-related diseases. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor.Methods: Samples of myometrium from term pregnant (≥37 weeks gestation) women were frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to identify the distribution of IL-33. Cultured cells were incubated with LPS to mimic inflammation as well as 4μ8C to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator.Results: Similar with onset of labor, LPS could reduce the expression of nuclear IL-33 in a time-limited manner and induced ER stress. Meanwhile, Knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of NF-κB and p38. In addition, siRNA IL-33 further simulates LPS enhanced COX-2 expression via NF-κB and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression. However, after IL-33 was knockdown, the stimulating effect of LPS on calcium was enhanced. 4μ8C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased accompanied by phosphorylated NF-κB and p38.Conclusions: These data suggest that IL-33 may be involved in initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells.

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

2014 ◽  
Vol 306 (9) ◽  
pp. H1314-H1323 ◽  
Author(s):  
Masayuki Koyama ◽  
Masato Furuhashi ◽  
Shutaro Ishimura ◽  
Tomohiro Mita ◽  
Takahiro Fuseya ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Er Stress ◽  
Systolic Pressure ◽  
Muscle Cells ◽  
Pulmonary Arterial ◽  
Phenylbutyric Acid

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH2-terminal kinase and eukaryotic translation initiation factor-2α in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.

scholarly journals Expression of Cyclooxygenase-2 and Prostanoid Receptors by Human Myometrium*

2000 ◽  
Vol 85 (9) ◽  
pp. 3468-3475 ◽  
Author(s):  
Tiina-Liisa Erkinheimo ◽  
Kirsi Saukkonen ◽  
Kirsi Narko ◽  
Jyrki Jalkanen ◽  
Olavi Ylikorkala ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Northern Blot ◽  
Blot Analysis ◽  
Northern Blot Analysis ◽  
Muscle Cells ◽  
Human Myometrium ◽  
Fetal Membranes ◽  
Prostanoid Receptors ◽  
Cox 2

Abstract Prostanoids play an important role in the regulation of parturition. All reproductive tissues, including fetal membranes, decidua, and myometrium, have the capacity to synthesize prostanoids, and fetal membranes have been shown to express elevated levels of cyclooxygenase-2 (Cox-2) at the onset of labor. We have now investigated the expression of Cox-2 in human myometrium. Myometrial samples collected from women in labor during lower segment cesarean section expressed 15-fold higher levels of Cox-2 messenger ribonucleic acid (mRNA) compared to myometrial specimens collected from women not in labor, as detected by Northern blot analysis. Immunohistochemical detection of Cox-2 protein showed cytoplasmic staining in the smooth muscle cells of the myometrium. Cultured myometrial cells expressed low levels of Cox-2 mRNA under baseline conditions, but interleukin-1β (IL-1β) caused a 17-fold induction of expression of the Cox-2 transcript after incubation for 6 h. IL-1β also induced expression of biologically active Cox-2 protein, as detected by immunofluorescence, Western blot analysis, and measuring the conversion of arachidonic acid to prostanoids in the presence and absence of a Cox-2-selective inhibitor, NS-398. PGE2 receptor subtype EP2 mRNA was expressed in cultured myometrial smooth muscle cells, whereas transcripts for EP1, EP3, EP4, FP, and IP were low or below the detection limit as measured by Northern blot analysis. However, IL-1β stimulated expression of EP4 receptor mRNA. Our data suggest that expression of Cox-2 transcript is elevated at the onset of labor in myometrial smooth muscle cells, which may depend on induction by cytokines. As, in addition to Cox-2, the expression of prostanoid receptors is regulated, not only the production of prostanoids, but also responsiveness to them, may be modulated.

Sorghum Fermented by Aspergillus oryzae NK Enhances Inhibition of Vascular Inflammation in TNF-α-stimulated Human Aortic Smooth Muscle Cells

2018 ◽  
Vol 88 (5-6) ◽  
pp. 309-318
Author(s):  
Hae Seong Song ◽  
Jung-Eun Kwon ◽  
Hyun Jin Baek ◽  
Chang Won Kim ◽  
Hyelin Jeon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Response ◽  
Smooth Muscle Cells ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Muscle Cells ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Tnf Α ◽  
Cox 2

Abstract. Sorghum bicolor L. Moench is widely grown all over the world for food and feed. The effects of sorghum extracts on general inflammation have been previously studied, but its anti-vascular inflammatory effects are unknown. Therefore, this study investigated the anti-vascular inflammation effects of sorghum extract (SBE) and fermented extract of sorghum (fSBE) on human aortic smooth muscle cells (HASMCs). After the cytotoxicity test of the sorghum extract, a series of experiments were conducted. The inhibition effects of SBE and fSBE on the inflammatory response and adhesion molecule expression were measured using treatment with tumor necrosis factor-α (TNF-α), a crucial promoter for the development of atherosclerotic lesions, on HASMCs. After TNF-α (10 ng/mL) treatment for 2 h, then SBE and fSBE (100 and 200 μg/mL) were applied for 12h. Western blotting analysis showed that the expression of vascular cell adhesion molecule-1 (VCAM-1) (2.4-fold) and cyclooxygenase-2 (COX-2) (6.7-fold) decreased, and heme oxygenase-1 (HO-1) (3.5-fold) increased compared to the TNF-α control when treated with 200 μg/mL fSBE (P<0.05). In addition, the fSBE significantly increased the expression of HO-1 and significantly decreased the expression of VCAM-1 and COX-2 compared to the TNF-α control in mRNA level (P<0.05). These reasons of results might be due to the increased concentrations of procyanidin B1 (about 6-fold) and C1 (about 30-fold) produced through fermentation with Aspergillus oryzae NK for 48 h, at 37 °C. Overall, the results demonstrated that fSBE enhanced the inhibition of the inflammatory response and adherent molecule expression in HASMCs.

Antibodies to cytokeratins bind to epitopes in human uterine smooth muscle cells in normal and pathological pregnancies

1995 ◽  
Vol 27 (5) ◽  
pp. 407-414 ◽  
Author(s):  
B. STIEMER ◽  
R. GRAF ◽  
H. NEUDECK ◽  
R. HILDEBRANDT ◽  
H. HOPP ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Uterine Smooth Muscle

scholarly journals The deregulation of STIM1 and store operative calcium entry impaired aortic smooth muscle cells contractility in aortic medial degeneration

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Junmou Hong ◽  
Zhipeng Hu ◽  
Qi Wu ◽  
Chaoliang Tang ◽  
Junxia Hu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Er Stress ◽  
Elastic Fiber ◽  
Muscle Cells ◽  
Cytoplasmic Calcium ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Medial Degeneration ◽  
Related Proteins

Abstract Background: Microarray analysis of clinical aortic samples suggested a potential role for stromal interaction molecule 1 (STIM1) in the modulation of aortic medial degeneration (AMD), despite the uncertainty about STIM1 in normal aortic smooth muscle cells (ASMCs). Here, we aimed to explore changes in STIM1 expression in AMD, and the possible mechanisms. Methods: An AMD model was established using auto-delivery of angiotensin II (Ang II) into ApoE−/− mice. We assessed the effects of SKF96365, a STIM1 inhibitor, in AMD model and in vitro cultured ASMCs. Elastic van Gieson (EVG) staining was used to visualize elastic fiber injury. Mitochondria changes were viewed by TEM. Cytoplasmic calcium was quantified by measuring fluo-4 staining in a flow cytometer. Mechanical stretching device was used to mimic stretching that ASMCs experience in vivo. Cell apoptosis was determined by using Annexin V/propidium iodide (PI) staining. The expression of STIM1, contractile related proteins (α-smooth muscle actin (α-SMA), myosin light chain (MLC)), endoplasmic reticulum (ER) stress-related proteins (CHOP, activating transcription factor 6 (ATF-6)) and smad2/3 were assessed by Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF). Results: SKF96365 exacerbated aortic injury in the AMD model. SKF96365 reduced cytoplasmic calcium concentration in ASMCs, caused mitochondrial swelling, and elevated the expression of ATF-6 and CHOP. SKF96365 decreased the expression of MLC and α-SMA in ASMCs, causing them to be vulnerable to mechanical stretch. SKF96365 suppressed smad2/3 activation after treatment with transforming growth factor (TGF) β1 (TGFβ1). Conclusions: STIM1 is indispensable in ASMCs. Interfering with STIM1 exaggerated the AMD process by modulating the expression of contractile proteins, inducing ER stress in ASMCs.

Abstract 443: Constitutive Bone Morphogenetic Protein 2-dependent Osteogenic Signaling in M1 Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Prabhatchandra Dube
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Er Stress ◽  
Vascular Calcification ◽  
Transient Receptor Potential ◽  
Muscle Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Osteogenic Potential ◽  
M1 Macrophages ◽  
Osteogenic Signaling

Atherosclerosis is the leading cause of carotid and coronary artery disease. Calcification often complicates atherosclerotic plaques and contributes to plaque instability.Mechanisms calcification are somewhat reminiscent of bone formation, involving interplay between endothelium, smooth muscle cells and plaque macrophages. Macrophages contribute to vascular calcification through signals that stimulate the osteogenic program in smooth muscle cells and/or by becoming osteoclast-like cells. Yet, the specific roles of polarized M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages, predominant in plaques, in lesion calcification remain poorly understood. Recent studies from our laboratory show that the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) is a key component of mechanisms linked to ER stress signaling in M1, but not M2 macrophages. Because ER stress has a recognized effect in inducing vascular calcification, we speculated that TRPC3, by virtue of its roles in M1 macrophages, might have an effect on the osteogenic potential of these cells. To address this question we utilized bone marrow derived macrophages from mice with macrophage-specific loss of TRPC3 function (MacTRPC3KO) or from their littermate controls (TRPC3 lox/lox ) and polarized in vitro to the M1 and M2 phenotypes. Osteogenic proteins and factors along with signaling mechanisms from the two groups were examined under basal and ER stress conditions. The results showed reduced expression of BMP-2 and Runx-2 at mRNA level in MacTRPC3KO M1 macrophages but not at the protein level between the groups. We also examined the phosphorylation status of SMAD1/5 in M1 macrophages, which is an early indicator of signaling downstream the BMP-2 receptor. Although no differences were observed between groups, SMAD1/5 was significantly phosphorylated, even under basal conditions. BMP-2 levels in supernatants from cultures of M1 macrophages was also significantly elevated regardless of the treatment condition. Notably, phosphorylation levels of SMAD1/5 were markedly reduced when cells were exposed to the BMP-2 receptor blocker dorsomorphin. These results indicate that BMP-2 is involved in activating osteogenic signaling in M1 macrophages.

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