Selected Contribution: Role of IL-6 in LPS-induced nuclear STAT3 translocation in sensory circumventricular organs during fever in rats

2002 ◽  
Vol 92 (6) ◽  
pp. 2657-2666 ◽  
Author(s):  
Eva-Maria Harré ◽  
Joachim Roth ◽  
Ulrich Pehl ◽  
Matthias Kueth ◽  
Rüdiger Gerstberger ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Systemic Circulation ◽  
Circumventricular Organs ◽  
Strong Increase ◽  
Molecular Evidence ◽  
Febrile Response ◽  
Sensory Structures ◽  
Transcription 3 ◽  
Lps Treatment

Interleukin-6 (IL-6) is regarded as an endogenous mediator of lipopolysaccharide (LPS)-induced fever. IL-6 is thought to act on the brain at sites that lack a blood-brain barrier, the circumventricular organs (CVOs). Cells that are activated by IL-6 respond with nuclear translocation of the signal transducer and activator of transcription 3 molecule (STAT3) and can be detected by immunohistochemistry. We investigated whether the LPS-induced release of IL-6 into the systemic circulation was accompanied by a nuclear STAT3 translocation within the sensory CVOs. Treatment with LPS (100 μg/kg) led to a slight (1 h) and then a strong increase (2–8 h) in plasma IL-6 levels, which started to decline at the end of the febrile response. Administration of both pyrogens LPS and IL-6 (45 μg/kg) induced a febrile response with IL-6, causing a rather moderate fever compared with the LPS-induced fever. Nuclear STAT3 translocation in response to LPS was observed within the vascular organ of the lamina terminalis (OVLT) and the subfornical organ (SFO) 2 h after LPS treatment. To investigate whether this effect was mediated by IL-6, the cytokine itself was systemically applied and indeed an identical pattern of nuclear STAT3 translocation was observed. However, nuclear STAT3 translocation already occurred 1 h after IL-6 application and proved to be less effective compared with LPS treatment when analyzing OVLT and SFO cell numbers that showed nuclear STAT3 immunoreactivity after the respective pyrogen treatment. Our observations represent the first molecular evidence for an IL-6-induced STAT3-mediated genomic activation of OVLT and SFO cells and support the proposed role of these brain areas as sensory structures for humoral signals created by the activated immune system and resulting in the generation of fever.

scholarly journals Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association

2019 ◽  
Vol 20 (8) ◽  
pp. 1949 ◽  
Author(s):  
Thu-Huyen Pham ◽  
Yesol Bak ◽  
Jae-Wook Oh ◽  
Jingi Hong ◽  
Seungyeoun Lee ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Additive Effects ◽  
Signal Transducer ◽  
Monocytic Cells ◽  
Kinase C ◽  
Direct Association ◽  
Transcription 3

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.

scholarly journals Role of STAT3 in Cancer Metastasis and Translational Advances

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Mohammad Zahid Kamran ◽  
Prachi Patil ◽  
Rajiv P. Gude
Keyword(s):  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Signal Transducer ◽  
Surface Receptors ◽  
Physiological Conditions ◽  
Stat3 Signaling ◽  
Tumor Growth And Metastasis ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.

Role of the MAPK and PI3-Kinase/Akt Pathways in the Pre-B Cell Receptor (pre-BCR)-Induced NF-κb Activation and Rag1 and Rag2 Down Regulation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2667-2667
Author(s):  
Kaiss Lassoued ◽  
Vincent Fuentes ◽  
Hussein Gamlouch ◽  
Eliane Bissac ◽  
Jean-Pierre Marolleau ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Conflicts Of Interest ◽  
Consensus Sequence ◽  
Pi3 Kinase ◽  
Strong Increase ◽  
Down Regulation

Abstract Abstract 2667 Poster Board II-643 The pre-BCR acts as a critical checkpoint in pre-B cell development and might be also involved in leukemogenesis. Using the 697 and Nalm6 human pre-B cell lines, we have previously shown that pre-BCR stimulation resulted in cell cycle progression associated with activation of number of adaptors and signaling pathways including the PI3-Kinase/Akt, Ras/MAPK, AP1 and the canonical NFkB pathway. We have also demonstrated that Src kinases together with Syk played a crucial role in controlling the pre-BCR-associated functions, acting upstream the above-mentioned signaling pathways. Pre-BCR crosslinking also induced down regulation of Rag1 and Rag2 transcription. In this study we aimed to evaluate the role of MAPK and Akt in the pre-BCR-induced NF-kB activation and Rag1/2 down modulation. For this purpose the 697 pre-B cells and normal bone marrow primary pre-B cells were treated with the U0126 and LY294002, and with MEK1/2 and Akt inhibitors, respectively. A dominant negative form of Akt fused to the HIV1 Tat peptide was also used to inhibit the PI3-Kinase/Akt pathway. We bring evidence that LY294002 could alter the pre-BCR-induced NF-kB activation by inhibiting : i) p105 degradation, ii) p50 NF-kB1 nuclear translocation and, iii) the binding of p50 to an oligonucleotide containing a specific consensus sequence. On the contrary, U0126 significantly enhanced p105 degradation, indicating that MAPK and Akt exerted antagonistic effects on the pre-BCR-induced NF-kB activation. Strikingly the baseline levels of Rag1 and Rag2 transcripts were increased in the LY294002 but not the U0126-treated pre-B cells. Futhermore, both inhibitors were shown to induce a strong increase in the expression of Rag1 and Rag2 transcripts upon pre-BCR crosslinking, suggesting that this receptor exerts dual effects on Rag1/2 expression with a predominant negative regulatory component mediated by both PI3-K and MAPK. No changes in the levels of Pax5, E2A, EBF, IFR4, IRF8, FOXO1, FOXO3, Myb, MAZ, LEF1 and SP1 (transcription factors implied in the regulation of Rag1 and Rag2 transcription) were observed in the pre-BCR stimulated or unstimulated-697 cells, treated or not with the MAPK and Akt inhibitors. Our results suggest that the pre-BCR signaling is a complex and tightly self-controlled process, which deregulation might alter cell growth and survival pathways via NF-kB as well as genomic stability trough Rag1/2 expression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Polyethylene Glycol 35 (PEG35) Modulates Exosomal Uptake and Function

Polymers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3044
Author(s):  
Ana Ferrero-Andrés ◽  
Daniel Closa ◽  
Joan Roselló-Catafau ◽  
Emma Folch-Puy
Keyword(s):  
Acute Pancreatitis ◽  
Biomedical Applications ◽  
Nuclear Translocation ◽  
Cell Types ◽  
Human Macrophage ◽  
Pathological Conditions ◽  
And Function ◽  
Transcription 3 ◽  
Inflammatory Effect

Polyethylene glycols (PEGs) are neutral polymers widely used in biomedical applications due to its hydrophilicity and biocompatibility. Exosomes are small vesicles secreted by nearly all cell types and play an important role in normal and pathological conditions. The purpose of this study was to evaluate the role of a 35-kDa molecular weight PEG (PEG35) on the modulation of exosome-mediated inflammation. Human macrophage-like cells THP-1, epithelial BICR-18, and CAPAN-2 cells were exposed to PEG35 prior to incubation with exosomes of different cellular origins. Exosome internalization was evaluated by confocal microscopy and flow cytometry. In another set of experiments, macrophages were treated with increasing concentrations of PEG35 prior to exposure with the appropriate stimuli: lipopolysaccharide, BICR-18-derived exosomes, or exosomes from acute pancreatitis-induced rats. Nuclear Factor Kappa B (NFκB) and Signal transducer and activator of transcription 3 (STAT3) activation and the expression levels of pro-inflammatory Interleukin 1β (IL1β) were determined. PEG35 administration significantly enhanced the internalization of exosomes in both macrophages and epithelial cells. Further, PEG35 ameliorated the inflammatory response induced by acute pancreatitis-derived exosomes by reducing the expression of IL1β and p65 nuclear translocation. Our results revealed that PEG35 promotes the cellular uptake of exosomes and modulates the pro-inflammatory effect of acute pancreatitis-derived vesicles through inhibition of NFκB, thus emphasizing the potential value of PEG35 as an anti-inflammatory agent for biomedical purposes.

Circulating signals as critical regulators of autonomic state—central roles for the subfornical organ

2010 ◽  
Vol 299 (2) ◽  
pp. R405-R415 ◽  
Author(s):  
Pauline M. Smith ◽  
Alastair V. Ferguson
Keyword(s):  
Blood Brain Barrier ◽  
Autonomic Function ◽  
Regulatory Peptides ◽  
Systemic Circulation ◽  
Circumventricular Organs ◽  
Subfornical Organ ◽  
Autonomic Control ◽  
Brain Barrier ◽  
Blood Brain

To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.

scholarly journals Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Tang ◽  
Mengchun Zhou ◽  
Rongrong Huang ◽  
Ling Shen ◽  
Li Yang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Astrocyte Activation ◽  
Hect Domain ◽  
P38 Inhibitor ◽  
Ubiquitin Protein Ligase ◽  
Primary Mouse ◽  
Lps Treatment

Abstract Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.

scholarly journals EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yiming He ◽  
Mingxi Gan ◽  
Yanan Wang ◽  
Tong Huang ◽  
Jianbin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

scholarly journals Fine Morphology of Antennal and Ovipositor Sensory Structures of the Gall Chestnut Wasp, Dryocosmus kuriphilus

Insects ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 231
Author(s):  
Milos Sevarika ◽  
Marco Valerio Rossi Stacconi ◽  
Roberto Romani
Keyword(s):  
Ultrastructural Organization ◽  
Antennal Sensilla ◽  
Dryocosmus Kuriphilus ◽  
Transmission Electron ◽  
Significant Damage ◽  
Sensory Structures ◽  
Host Plant Location ◽  
Oviposition Sites ◽  
Fine Morphology

Dryocosmus kuriphilus is a gall-inducing insect, which can cause significant damage on plants of the genus Castanea Mill., 1754. Antennae and ovipositor are the main sensory organs involved in the location of suitable oviposition sites. Antennal sensilla are involved in the host plant location, while ovipositor sensilla assess the suitability of the ovipositional bud. On both organs, diverse sensillar organs are present. Here, the distribution and ultrastructural organization of the sensilla were investigated by scanning and transmission electron microscopy. The antennae of D. kuriphilus are filiform and composed of 14 antennomeres, with the distal flagellomere bearing the highest number of sensilla. On the antennae, 6 sensilla types were found; sensilla chaetica, campaniformia, coeloconica-I, coeloconica-II, trichoidea and placoidea. The sensilla placoidea and trichoidea were the most abundant types. On the external walls of the ovipositor, gustatory and mechanoreceptive sensilla were observed. Internally, the egg channel hosted two additional sensory structures. The putative functional role of each sensilla in the context of insect’s ecology is discussed as well as the ovipositional mechanism used by this insect.

scholarly journals Phaseolin Attenuates Lipopolysaccharide-Induced Inflammation in RAW 264.7 Cells and Zebrafish

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 420
Author(s):  
Su-Jung Hwang ◽  
Ye-Seul Song ◽  
Hyo-Jong Lee
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Raw 264.7 Cells ◽  
Network Pharmacology ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Bioactive Constituents

Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, the role of phaseolin (one of the primary components of S. flavescentis) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation.

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