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Inflammasome phosphorylation

Jawed Iqbal, Mairaj Ahmed Ansari, Binod Kumar, Dipanjan Dutta, Arunava Roy, Leela Chikoti, Gina Pisano, Sujoy Dutta, Shahrooz Vahedi, Mohanan Valiya Veettil, Bala Chandran
IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1β and antiviral type-1 interferon-β (IFN-β) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1β generation...
October 2016: PLoS Pathogens
Andrea Villar-Lorenzo, Alejandro E Ardiles, Ana I Arroba, Enrique Hernández-Jiménez, Virginia Pardo, Eduardo López-Collazo, Ignacio A Jiménez, Isabel L Bazzochi, Águeda González-Rodríguez, Ángela M Valverde
A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB)...
October 14, 2016: Toxicology and Applied Pharmacology
Weijie Chen, Junlian Wang, Yong Luo, Tao Wang, Xiaochun Li, Aiyun Li, Jia Li, Kang Liu, Baolin Liu
BACKGROUND: This study was designed to investigate whether ginsenoside Rb1 (Rb1) and compound K (CK) ameliorated insulin resistance by suppressing endoplasmic reticulum (ER) stress-induced inflammation in adipose tissue. METHODS: To induce ER stress, epididymal adipose tissue from mice or differentiated 3T3 adipocytes were exposed to high glucose. The effects of Rb1 and CK on reactive oxygen species production, ER stress, TXNIP/NLRP3 inflammasome activation, inflammation, insulin signaling activation, and glucose uptake were detected by western blot, emzyme-linked immunosorbent assay, or fluorometry...
October 2016: Journal of Ginseng Research
Peipei Zhang, Kohsuke Tsuchiya, Takeshi Kinoshita, Hiroko Kushiyama, Sofya Suidasari, Mizuki Hatakeyama, Hisanori Imura, Norihisa Kato, Takashi Suda
Vitamin B6 includes six water-soluble vitamers: pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), and their phosphorylated forms. Pyridoxal 5'-phosphate (PLP) is an important cofactor for many metabolic enzymes. Several lines of evidence demonstrate that blood levels of PLP are significantly lower in patients with inflammation than in control subjects, and that vitamin B6 has anti-inflammatory effects, with therapeutic potential for a variety of inflammatory diseases. Although one of our group (NK) previously demonstrated that PL inhibits the NF-κB pathway, the molecular mechanism by which vitamin B6 suppresses inflammation is not well understood...
October 12, 2016: Journal of Biological Chemistry
Yeon-Ho Chung, Dong-Hyun Kim, Won-Woo Lee
IL-1β is a key mediator of sterile inflammation in response to endogenous particulates, a type of damage-associated molecular pattern (DAMPs) molecule derived from damaged cells. Despite the well-known role of sterile particulates such as monosodium urate (MSU) crystals as inflammasome inducers in monocytes/macrophages, little is known regarding how pro-IL-1β synthesis is induced under sterile inflammatory conditions. We provide evidence that MSU crystals post-transcriptionally induce the rapid production of pro-IL-1β in human primary monocytes...
October 3, 2016: Scientific Reports
Chuansheng Guo, Shujun Xie, Zhexu Chi, Jinhua Zhang, Yangyang Liu, Li Zhang, Mingzhu Zheng, Xue Zhang, Dajing Xia, Yuehai Ke, Linrong Lu, Di Wang
Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptor-induced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291...
September 26, 2016: Immunity
Lawton K Chung, Yong Hwan Park, Yueting Zheng, Igor E Brodsky, Patrick Hearing, Daniel L Kastner, Jae Jin Chae, James B Bliska
Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown...
September 14, 2016: Cell Host & Microbe
Leanne Mortimer, France Moreau, Justin A MacDonald, Kris Chadee
Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function...
October 2016: Nature Immunology
Madathilparambil V Suresh, Bivin Thomas, David Machado-Aranda, Vladislov A Dolgachev, Sadeesh Kumar Ramakrishnan, Nicholas Talarico, Karen Cavassani, Matthew A Sherman, Mark R Hemmila, Steven L Kunkel, Nils G Walter, Cory M Hogaboam, Krishnan Raghavendran
OBJECTIVES: Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. We set to determine the role of toll-like receptor 3 and the binding of double-stranded RNA in the pathogenesis of sterile injury following lung contusion. DESIGN: Toll-like receptor 3 expression was analyzed in postmortem lung samples from patients with lung contusion. Unilateral lung contusion was induced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-β (-/-), and wild-type mice...
November 2016: Critical Care Medicine
Shuchao Wang, Zedong Wang, Yi Gu, Zhongyu Li, Zhongyuan Li, Feng Wei, Quan Liu
Toxoplasma gondii can activate the nucleotide-binding domain and leucine-rich repeat-containing proteins NLRP1/3 inflammasomes, which mediate host resistance to the infection. Here we showed that deletion of mitogen-activated protein kinases MAPK1 and MAPK2 of type I parasite decreases acute virulence in mice, characterized by low levels of interleukin (IL)-18, NLRP1/3, ASC, and caspase-1, and high levels of IL-10 and interferon (IFN)-β transcripts. Additionally, the mutants increased phosphorylation of STAT1, and decreased phosphorylation of STAT3...
July 27, 2016: Microbes and Infection
Shi Yue, Jianjun Zhu, Ming Zhang, Changyong Li, Xingliang Zhou, Min Zhou, Michael Ke, Ronald W Busuttil, Qilong Ying, Jerzy W Kupiec-Weglinski, Qiang Xia, Bibo Ke
: Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. β-catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1-β-catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia and reperfusion injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1-β-catenin signaling influenced the NLRP3-mediated innate immune response in vivo and in vitro...
July 30, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Kristen T Crowell, Jennifer L Steiner, Catherine S Coleman, Charles H Lang
BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet...
September 2016: Alcoholism, Clinical and Experimental Research
Laura R Hoyt, Jennifer L Ather, Matthew J Randall, Daniel P DePuccio, Christopher C Landry, Mark D Wewers, Mikhail A Gavrilin, Matthew E Poynter
Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multiprotein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the proinflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol, and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow-derived dendritic cells, mouse neutrophils, and human PBMCs...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Niamh P Healy, Anna M Kirwan, Maeve A McArdle, Kieran Holohan, Alice B Nongonierma, Deirdre Keane, Stacey Kelly, Lucia Celkova, Claire L Lyons, Fiona C McGillicuddy, Orla M Finucane, Brian A Murray, Philip M Kelly, Lorraine Brennan, Richard J FitzGerald, Helen M Roche
SCOPE: Activation of the nod-like receptor protein 3 (NLRP3)-inflammasome is required for IL-1β release and is a key component of obesity-induced inflammation and insulin resistance (IR). This study hypothesized that supplementation with a casein hydrolysate (CH) would attenuate NLRP3-inflammasome mediated IL-1β secretion in adipose tissue (AT) and improve obesity-induced IR. METHODS AND RESULTS: J774.2 macrophages were LPS primed (10ng/ml) and stimulated with adenosine triphosphate (ATP) (5mM) to assess NLRP3 inflammasome activity...
July 8, 2016: Molecular Nutrition & Food Research
Nagisa Okada, Chifumi Fujii, Tomio Matsumura, Masato Kitazawa, Ryuhei Okuyama, Shun'ichiro Taniguchi, Shigeaki Hida
Disorders of cytoskeletal remodeling and signal transduction are frequently involved in cancer progression. In particular, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) has been reported a proapoptotic molecule that is epigenetically silenced in several human cancers. ASC is a well-characterized adaptor protein involved in the formation of multiprotein oligomers, called inflammasomes, and plays a crucial role in the activation and secretion of interleukin-1β and interleukin-18 in innate immune cells...
September 2016: Cancer Medicine
Terence N Bukong, Arvin Iracheta-Vellve, Banishree Saha, Aditya Ambade, Abhishek Satishchandran, Benedek Gyongyosi, Patrick Lowe, Donna Catalano, Karen Kodys, Gyongyi Szabo
UNLABELLED: The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, which has a central modulatory role in multiple proinflammatory signaling pathways involved in the pathomechanism of ALD...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Aiyun Li, Shuihong Zhang, Jia Li, Kang Liu, Fang Huang, Baolin Liu
OBJECTIVE: This study was designed to investigate the hypothesis that metformin and resveratrol exhibited the same effect on inhibition of NLRP3 inflammasome activation with regulation of AMPK in adipose tissue exposed to high glucose. METHODS: To induce adipose tissue dysfunction, we treated epididymal adipose tissue of mice or differentiated 3T3-L1 adipocytes with high glucose (33 mM) for 24 h. Meanwhile, mice were injected with streptozotocin STZ to induce diabetes and followed by oral administration of metformin (200 mg/kg), resveratrol (50 mg/kg) or ER stress inhibitor TUDCA (50 mg/kg) for 7 days...
October 15, 2016: Molecular and Cellular Endocrinology
Yong Hwan Park, Geryl Wood, Daniel L Kastner, Jae Jin Chae
Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome...
August 2016: Nature Immunology
Lin-Lin Kang, Dong-Mei Zhang, Chun-Hua Ma, Jian-Hua Zhang, Ke-Ke Jia, Jia-Hui Liu, Rong Wang, Ling-Dong Kong
Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury, and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis...
2016: Scientific Reports
Ji-Won Han, Do-Wan Shim, Woo-Young Shin, Myong-Ki Kim, Eun-Jeong Shim, Xiao Sun, Sushruta Koppula, Tack-Joong Kim, Tae-Bong Kang, Kwang-Ho Lee
ETHNOPHARMACOLOGICAL RELEVANCE: Juniperus rigida Sieb. (J. rigida) is used for medicinal purposes in Asian countries to treat inflammation-related disorders, such as neuralgia, dropsy, and gout. AIM OF THE STUDY: The anti-inflammatory effects of J. rigida extract (JR) and its underlying mechanisms were explored both in in vitro cell lines and in vivo metabolic disease models. MATERIAL AND METHODS: Lipopolysaccharide (LPS)-stimulated RAW264...
August 22, 2016: Journal of Ethnopharmacology
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