scholarly journals Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ Failure during Acute Polymicrobial Sepsis

2007 ◽  
Vol 75 (4) ◽  
pp. 1690-1697 ◽  
Author(s):  
Georg F. Weber ◽  
Sylvia Schlautkötter ◽  
Simone Kaiser-Moore ◽  
Felicitas Altmayr ◽  
Bernhard Holzmann ◽  
...  
Keyword(s):  
Organ Failure ◽  
Bacterial Load ◽  
Kidney Injury ◽  
Mononuclear Phagocytes ◽  
Pcr Analysis ◽  
Interleukin 22 ◽  
Septic Peritonitis

ABSTRACT Interleukin-22 (IL-22) is a recently discovered proinflammatory cytokine, structurally related to IL-10. Since IL-22 is induced by lipopolysaccharide in vivo, we studied the role of IL-22 in a model of polymicrobial peritonitis. Quantitative real-time reverse transcription-PCR analysis showed marked induction of IL-22 and IL-22 receptor in spleen and kidney during the course of sepsis. The biological activity of IL-22 is modulated by IL-22-binding protein (IL-22BP), which is considered a natural antagonist of IL-22. To further analyze the role of IL-22 during septic peritonitis, mice were treated with recombinant IL-22BP generated as Fcγ2a fusion protein. IL-22BP-Fc completely blocked IL-22-induced STAT3 activation in hepatocytes in vitro. Treatment of mice with IL-22BP-Fc 4 h before sepsis induction led to enhanced accumulation of neutrophils and mononuclear phagocytes and a reduced bacterial load at the site of infection. In addition, IL-22 blockade led to an enhanced bacterial clearance in liver and kidney and reduced kidney injury. These results imply an important proinflammatory role of IL-22 during septic peritonitis, contributing to bacterial spread and organ failure. IL-22 therefore appears to play an important role in the regulation of inflammatory processes in vivo.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

Multinucleated rat alveolar macrophages express functional receptors for calcitonin

1991 ◽  
Vol 261 (6) ◽  
pp. F1026-F1032 ◽  
Author(s):  
A. Vignery ◽  
M. J. Raymond ◽  
H. Y. Qian ◽  
F. Wang ◽  
S. A. Rosenzweig
Keyword(s):  
Plasma Membrane ◽  
Alveolar Macrophages ◽  
Giant Cells ◽  
Mononuclear Phagocytes ◽  
Inflammatory Reactions ◽  
Calcitonin Gene ◽  
Novel Model

The fusion of mononuclear phagocytes occurs spontaneously in vivo and leads to the differentiation of either multinucleated giant cells or osteoclasts in chronic inflammatory sites or in bone, respectively. Although osteoclasts are responsible for resorbing bone, the functional role of giant cells in chronic inflammatory reactions and tumors remains poorly understood. We recently reported that the plasma membrane of multinucleated macrophages is, like that of osteoclasts, enriched in Na-K-adenosinetriphosphatases (ATPases). We also observed that the localization of their Na-K-ATPases is restricted to the nonadherent domain of the plasma membrane of cells both in vivo and in vitro, thus imposing a functional polarity on their organization. By following this observation, we wished to investigate whether these cells also expressed, like osteoclasts, functional receptors for calcitonin (CT). To this end, alveolar macrophages were fused in vitro, and both their structural and functional association with CT was analyzed and compared with those of mononucleated peritoneal and alveolar macrophages. Evidence is presented that multinucleated alveolar macrophages express a high copy number of functional receptors for CT. Our results also indicate that alveolar macrophages, much like peritoneal, express functional receptors for calcitonin gene-related peptide. It is suggested that multinucleated rat alveolar macrophages offer a novel model system to study CT receptors and that calcitonin may control local immune reactions where giant cells differentiate.

scholarly journals Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

2017 ◽  
Vol 214 (4) ◽  
pp. 905-917 ◽  
Author(s):  
Yochai Wolf ◽  
Anat Shemer ◽  
Michal Polonsky ◽  
Mor Gross ◽  
Alexander Mildner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mononuclear Phagocytes ◽  
Autoimmune Encephalomyelitis ◽  
Wild Type Counterpart ◽  
And Function ◽  
Necrosis Factor ◽  
Experimental Autoimmune

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function.

scholarly journals The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 20 (20) ◽  
pp. 5238 ◽  
Author(s):  
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Smaranda Radu ◽  
Claudia Florida Costea ◽  
Manuela Ciocoiu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

scholarly journals Activation of LncRNA HOTAIR by STAT3 Promotes Gefitinib Resistance and Tumourigenesis by Targeting MicroRNA-216a in NSCLC

2021 ◽  
Author(s):  
Hongge Zhu ◽  
Xiuli Wang ◽  
Xin Zhou ◽  
Suqiong Lu ◽  
Guomin Gu ◽  
...  
Keyword(s):  
Nsclc Patient ◽  
Bioinformatic Analysis ◽  
Luciferase Assay ◽  
Pcr Analysis ◽  
Nsclc Patients ◽  
Gefitinib Resistance ◽  
Lncrna Hotair

Abstract Background: Gefitinib resistance has become a major obstacle for cancer therapy of non-small cell lung cancer (NSCLC). Exosome-mediated transfer of long noncoding RNAs (lncRNAs) is associated with the drug-resistance in various tumors. However, the role of NSCLC-specific exosomal lncRNAs remains largely unknown. The aim of this study is to explore the role of exosomal Hox transcript antisense intergenic RNA (HOTAIR) on gefitinib resistance in NSCLC. Methods: We investigated the expression of lncRNAs in 5 paired gefitinib-sensitive and gefitinib-resistant tissues of NSCLC by microarray analysis. The qRT-PCR analysis was to investigate the expression pattern of HOTAIR in gefitinib-resistant NSCLC patient tissues and cell lines. Then, we investigated the effects of HOTAIR on gefitinib resistance in vitro and in vivo. Results: In this study, we found HOTAIR was evidently up-regulated in both tissues and serum exosome of gefitinib-resistant NSCLC patients. Moreover, by knocking down HOTAIR, we found that HOTAIR promoted the proliferation of NSCLC cells in vitro, as well as inhibited cell apoptosis and cell sensitivity to gefitinib. Extracellular HOTAIR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminated gefitinib resistance. The expression level of HOTAIR from circulating exosomes is significantly higher in NSCLC patients with gefitinib resistance than those without gefitinib resistance. Mechanistically, bioinformatic analysis coupled with dual luciferase assay revealed that HOTAIR served as miR-216a sponge, and MAP1S was identified as a functional target of miR-216a. Conclusions: In conclusion, these data suggest that exosomal HOTAIR serves as an oncogenic role in gefitinib resistance of NSCLC cells CRC through activating miR-216a/MAP1S signaling pathway, providing a novel avenue for the treatment of NSCLC.

scholarly journals A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Amol K Bhandage ◽  
Gabriela C Olivera ◽  
Sachie Kanatani ◽  
Elizabeth Thompson ◽  
Karin Loré ◽  
...  
Keyword(s):  
Neospora Caninum ◽  
Mononuclear Phagocytes ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Voltage Dependent ◽  
Coccidian Parasites ◽  
Voltage Dependent Calcium Channels

Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.

scholarly journals Cyclooxygenase-2 Regulated by the Nuclear Factor-κB Pathway Plays an Important Role in Endometrial Breakdown in a Female Mouse Menstrual-like Model

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2900-2911 ◽  
Author(s):  
Xiangbo Xu ◽  
Xihua Chen ◽  
Yunfeng Li ◽  
Huizi Cao ◽  
Cuige Shi ◽  
...  
Keyword(s):  
Critical Role ◽  
Nuclear Factor Κb ◽  
Pcr Analysis ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Cox Inhibitor ◽  
Cox 2

Abstract The role of prostaglandins (PGs) in menstruation has long been proposed. Although evidence from studies on human and nonhuman primates supports the involvement of PGs in menstruation, whether PGs play an obligatory role in the process remains unclear. Although cyclooxygenase (COX) inhibitors have been used in the treatment of irregular uterine bleeding, the mechanism involved has not been elucidated. In this study, we used a recently established mouse menstrual-like model for investigating the role of COX in endometrial breakdown and its regulation. Administration of the nonspecific COX inhibitor indomethacin and the COX-2 selective inhibitor DuP-697 led to inhibition of the menstrual-like process. Furthermore, immunostaining analysis showed that the nuclear factor (NF)κB proteins P50, P65, and COX-2 colocalized in the outer decidual stroma at 12 to 16 hours after progesterone withdrawal. Chromatin immunoprecipitation analysis showed that NFκB binding to the Cox-2 promoter increased at 12 hours after progesterone withdrawal in vivo, and real-time PCR analysis showed that the NFκB inhibitors pyrrolidine dithiocarbamate and MG-132 inhibited Cox-2 mRNA expression in vivo and in vitro, respectively. Furthermore, COX-2 and NFκB inhibitors similarly reduced endometrial breakdown, suggesting that NFκB/COX-2-derived PGs play a critical role in this process. In addition, the CD45+ leukocyte numbers were sharply reduced following indomethacin (COX-1 and COX-2 inhibitor), DuP-697 (COX-2 inhibitor), and pyrrolidine dithiocarbamate (NFκB inhibitor) treatment. Collectively, these data indicate that NFκB/COX-2-induced PGs regulate leukocyte influx, leading to endometrial breakdown.

scholarly journals Blocking of progestin action disrupts spermatogenesis in Nile tilapia (Oreochromis niloticus)

2014 ◽  
Vol 53 (1) ◽  
pp. 57-70 ◽  
Author(s):  
Gang Liu ◽  
Feng Luo ◽  
Qiang Song ◽  
Limin Wu ◽  
Yongxiu Qiu ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Oreochromis Niloticus ◽  
Nile Tilapia ◽  
Phylogenetic Analyses ◽  
Pcr Analysis ◽  
Steroidogenic Enzymes ◽  
Spermatogonial Cell

In vitrostudies have indicated that the maturation-inducing hormone 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-DP, DHP), probably through nuclear progestin receptor (Pgr), might be involved in the proliferation of spermatogonial cells and the initiation of meiosis in several fish species. However, furtherin vivoevidence is required to elucidate the role of DHP in spermatogenesis during sexual differentiation in teleosts. In this study, we clonedpgrand analyzed its expression in Nile tilapia (Oreochromis niloticus) and treated XY fish with RU486 (a synthetic Pgr antagonist) from 5 days after hatching (dah) to determine the role of DHP in spermatogenesis. Sequence and phylogenetic analyses revealed that the Pgr identified in tilapia is a genuine Pgr. Pgr was found to be expressed in the Sertoli cells surrounding spermatogonia and spermatids in the testis of tilapia. Real-time PCR analysis revealed that the expression ofpgrin the testis was significantly upregulated from 10 dah, further increased at 50 dah, and persisted until adulthood in fish. In the testis of RU486-treated fish, the transcript levels of germ cell markers and a meiotic marker were substantially reduced. However, the expression of markers in Sertoli cells remained unchanged. Moreover, the production of 11-ketotestosterone and the expression of genes encoding various steroidogenic enzymes were also not altered. In contrast, the expression ofcyp17a2, encoding one of the critical steroidogenic enzymes involved in DHP biosynthesis, declined significantly, possibly indicating the inhibition of DHP production by RU486. RU486 treatment given for 2 months did not affect spermatogenesis; however, treatment given for more than 3 months resulted in a decrease in spermatogonial cell numbers and depletion of later-phase spermatogenic cells. Simultaneous excessive DHP supplementation restored spermatogenesis in RU486-treated XY fish. Taken together, our data further indicated that DHP, possibly through Pgr, might be essential for spermatogonial cell proliferation and spermatogenesis in fish.

Metabolomic Analysis of SCD During Goose Follicular Development: Implications for Lipid Metabolism

2020 ◽  
Author(s):  
Xin Yuan ◽  
Shenqiang Hu ◽  
Liang Li ◽  
Hehe Liu ◽  
Hua He ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Expression Patterns ◽  
Follicular Development ◽  
Pcr Analysis ◽  
Qrt Pcr ◽  
Preovulatory Follicles ◽  
Liquid Chromatography Tandem Mass

Abstract Background Stearoyl-CoA desaturase (SCD) is known to be an important rate-limiting enzyme in the production of MUFA. The role of this enzyme in goose follicular development is poorly understood. To investigate the metabolic mechanism of SCD during goose follicular development, we observed SCD expression patterns during follicular development in vivo and in vitro using quantitative reverse-transcription (qRT)-PCR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine a cellular model of SCD function in granulosa cells (GCs) via SCD overexpression and knockdown.Results qRT-PCR analysis showed that SCD was abundantly expressed in the GC layer, and was upregulated in preovulatory follicles. Peak expression was found in F1 and prehierarchal follicles with diameters of 4–6 mm and 8–10 mm, respectively. We further found the mRNA expression and corresponding enzyme activity to occur in a time-dependent oscillation in vitro, beginning on the first day of GC culture. By using LC-MS/MS, we identified numerous changes in metabolite activation and developed an overview of multiple metabolic pathways, ten of which were associated with lipid metabolism and enriched in both the overexpressed and the knockdown groups.ConclusionsWe confirmed cholesterol and pantothenol or pantothenate as potential metabolite biomarkers for studying SCD-related lipid metabolism in goose GCs.

scholarly journals Role of TRPA1 in Tissue Damage and Kidney Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3415
Author(s):  
Chung-Kuan Wu ◽  
Ji-Fan Lin ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Kidney Disease ◽  
Tissue Damage ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cell Types ◽  
Renal Tubular

TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.

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