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Interleukin receptor associated kinase m

Peipei Jin, Lulong Bo, Yongjian Liu, Wenbin Lu, Shengwei Lin, Jinjun Bian, Xiaoming Deng
Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator for Toll-like receptor signaling, which can regulate immune homeostasis and tolerance in a number of pathological settings. However, the mechanism for IRAK-M regulation at transcriptional level remains largely unknown. In this study, a 1.4kb upstream sequence starting from the major IRAK-M transcriptional start site was cloned into luciferase reporter vector pGL3-basic to construct the full-length IRAK-M promoter. Luciferase reporter plasmids harboring the full-length and the deletion mutants of IRAK-M were transfected into 293T and A549 cells, and their relative luciferase activity was measured...
August 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Weiguo Dong, Christine M Embury, Yaman Lu, Sarah M Whitmire, Bhagyalaxmi Dyavarshetty, Harris A Gelbard, Howard E Gendelman, Tomomi Kiyota
BACKGROUND: Amyloid-β (Aβ)-stimulated microglial inflammatory responses engage mitogen-activated protein kinase (MAPK) pathways in Alzheimer's disease (AD). Mixed-lineage kinases (MLKs) regulate upstream MAPK signaling that include p38 MAPK and c-Jun amino-terminal kinase (JNK). However, whether MLK-MAPK pathways affect Aβ-mediated neuroinflammation is unknown. To this end, we investigated if URMC-099, a brain-penetrant small-molecule MLK type 3 inhibitor, can modulate Aβ trafficking and processing required for generating AD-associated microglial inflammatory responses...
2016: Journal of Neuroinflammation
J H Kim, J H Park, M Eisenhut, J W Yu, J I Shin
Inflammasomes are caspase-1-activating molecular platforms that produce active interleukin (IL)-1β and are implicated in various central nervous system (CNS) diseases. These multi-protein complexes can be activated by exposure of cells to low osmolality. The inflammasome nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) is hereby the main sensor of cellular osmolality. IL-1β was found to stimulate the secretion of antidiuretic hormone (ADH) from the posterior pituitary gland either by action of prostaglandins or indirectly by causing the release of IL-6...
August 2016: Medical Hypotheses
Bruce Teter, Mary Jo LaDu, Patrick M Sullivan, Sally A Frautschy, Greg M Cole
The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling is modulated by ApoE and observed in AD, ApoE isotype-specific effects remain poorly understood. Therefore, we examined the effect of the ApoE isotype on the brain levels of major regulators of TLR signaling including miR146a, a microRNA enriched in the brain...
August 3, 2016: Neuroreport
Oliver H Voss, Yousuke Murakami, Mirna Y Pena, Ha-Na Lee, Linjie Tian, David H Margulies, Jonathan M Street, Peter S T Yuen, Chen-Feng Qi, Konrad Krzewski, John E Coligan
Receptor CD300b is implicated in regulating the immune response to bacterial infection by an unknown mechanism. Here, we identified CD300b as a lipopolysaccharide (LPS)-binding receptor and determined the mechanism underlying CD300b augmentation of septic shock. In vivo depletion and adoptive transfer studies identified CD300b-expressing macrophages as the key cell type augmenting sepsis. We showed that CD300b, and its adaptor DAP12, associated with Toll-like receptor 4 (TLR4) upon LPS binding, thereby enhancing TLR4-adaptor MyD88- and TRIF-dependent signaling that resulted in an elevated pro-inflammatory cytokine storm...
June 21, 2016: Immunity
K L Becker, V Aimanianda, X Wang, M S Gresnigt, A Ammerdorffer, C W Jacobs, R P Gazendam, L A B Joosten, M G Netea, J P Latgé, F L van de Veerdonk
UNLABELLED: Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus Transcription and production of the proinflammatory cytokine interleukin-1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively...
2016: MBio
Karina S MacDowell, Javier R Caso, David Martín-Hernández, Beatriz M Moreno, José L M Madrigal, Juan A Micó, Juan C Leza, Borja García-Bueno
Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stress-induced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples...
May 27, 2016: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Doreen M Floss, Tobias Klöcker, Jutta Schröder, Larissa Lamertz, Simone Mrotzek, Birgit Strobl, Heike Hermanns, Jürgen Scheller
The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor β1 (IL-12Rβ1) as one component of their receptor signaling complexes, with IL-12Rβ2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12Rβ1, whereas Jak2 binds to IL-23R and also to IL-12Rβ2...
July 15, 2016: Molecular Biology of the Cell
M Hajivalili, F Pourgholi, J Majidi, L Aghebati-Maleki, A A Movassaghpour, H Samadi Kafil, A Mirshafiey, M Yousefi
Inflammation is inseparable part of different diseases especially cancer and autoimmunity. During inflammation process toll like receptor 4(TLR4) responds to lipopolysaccharide (LPS), one of the bacterial components, and TLR4 signaling leads to interleukine-1 receptor associated kinase-1 (IRAK1) and tumor necrosis factor (TNF) receptor associated factor6 (TRAF6) activation which ultimately results in nuclear factor- ĸB (NF-ĸB) activation as the main transcription factor of inflammatory cytokines. Conversely, NF-ĸB over activation induces miR-146a in innate immune cells which can consequently reduce TRAF6, IRAK1, and NF-ĸB activation in a negative feedback...
2016: Cellular and Molecular Biology
Chen Wang, Xiao-Xi Liu, Kai-Bin Huang, Su-Bing Yin, Jing-Jing Wei, Ya-Fang Hu, Yong Gu, Guo-Qing Zheng
Preconditioning with ligands of toll-like receptors (TLRs) is a powerful neuroprotective approach whereby a low dose of stimulus confers significant protection against subsequent substantial brain damage by reprogramming the ischemia-activated TLRs signaling. Herein, we aim to explore whether preconditioning with recombinant high-mobility group box 1 (rHMGB1), one of the TLRs ligands, decreases cerebral ischemia-reperfusion injury (IRI). Rats were intracerebroventricularly pretreated with rHMGB1, 1 or 3 days before induction of middle cerebral artery occlusion...
May 2016: Journal of Neurochemistry
Heather A Frey, Molly J Stout, Laurel N Pearson, Methodius G Tuuli, Alison G Cahill, Jerome F Strauss, Luis M Gomez, Samuel Parry, Jenifer E Allsworth, George A Macones
BACKGROUND: Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. OBJECTIVE: The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women...
August 2016: American Journal of Obstetrics and Gynecology
Brendan M Gabriel, D Lee Hamilton, Annie M Tremblay, Henning Wackerhage
The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6...
May 15, 2016: Journal of Applied Physiology
Chase Cawyer, Syeda H Afroze, Nathan Drever, Steven Allen, Richard Jones, David C Zawieja, Thomas Kuehl, M Nasir Uddin
OBJECTIVE: Preeclampsia (preE) is a hypertensive disorder that occurs 20% in diabetic pregnancy. We have shown that hyperglycemia impairs cytotrophoblast cell (CTB) function. In this study, we assess apoptotic and anti-angiogenic signaling in excess glucose-induced CTBs. STUDY DESIGN: Human extravillous CTBs (Sw. 71) were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with a p38 inhibitor (SB203580) or a peroxisome proliferator-activated receptor gamma (PPARγ) ligand (rosiglitazone) or with D-mannitol...
May 2016: Hypertension in Pregnancy
E Eftekhar, M Doustaki Zaboli, M Katebi, F Ghadiri Soufi
OBJECTIVES: This study was conducted to explore whether microRNA-146a and its adapter proteins (TNF-α receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1)) are affected by diabetes in the rat heart. METHODS: Twelve male Sprague-Dawley rats were randomized into control and diabetic groups (n = 6). Streptozotocin-nicotinamide experimental model was used to induce type 2 diabetes. The gene expression of MicroRNA-146a, nuclear factor-κB (NF-κB), IRAK1 and TRAF6, as well as NF-κB activity, IRAK1 and TRAF6 protein levels were measured...
2016: Bratislavské Lekárske Listy
Xiao Wang, Mikael Sjölinder, Yumin Gao, Yi Wan, Hong Sjölinder
UNLABELLED: Neisseria meningitidis colonizes the nasopharyngeal mucosa of healthy populations asymptomatically, although the bacterial surface is rich in motifs that activate the host innate immunity. What determines the tolerant host response to this bacterium in asymptomatic carriers is poorly understood. We demonstrated that the conserved meningococcal surface protein NhhA orchestrates monocyte (Mo) differentiation specifically into macrophage-like cells with a CD200R(hi) phenotype (NhhA-Mφ)...
2016: MBio
Sen Liu, Qiuyang Zhang, Chong Chen, Dongxia Ge, Yine Qu, Rongyi Chen, Yi-Ming Fan, Nan Li, Wendell W Tang, Wensheng Zhang, Kun Zhang, Alun R Wang, Brian G Rowan, Steven M Hill, Oliver Sartor, Asim B Abdel-Mageed, Leann Myers, Qishan Lin, Zongbing You
Interleukin-17 (IL-17) plays important roles in inflammation, autoimmune diseases, and some cancers. Obese people are in a chronic inflammatory state with increased serum levels of IL-17, insulin, and insulin-like growth factor 1 (IGF1). How these factors contribute to the chronic inflammatory status that promotes development of aggressive prostate cancer in obese men is largely unknown. We found that, in obese mice, hyperinsulinemia enhanced IL-17-induced expression of downstream proinflammatory genes with increased levels of IL-17 receptor A (IL-17RA), resulting in development of more invasive prostate cancer...
March 22, 2016: Oncotarget
Ryan J Stark, Hyehun Choi, Stephen R Koch, Benjamin A Fensterheim, Fred S Lamb, Edward R Sherwood
Prior exposure to lipopolysaccharide (LPS) produces a reduced or "tolerant" inflammatory response to subsequent challenges with LPS, however the potent pro-inflammatory effects of LPS limit its clinical benefit. The adjuvant monophosphoryl lipid A (MPLA) is a weak toll-like receptor 4 (TLR4) agonist that induces negligible inflammation but retains potent immunomodulatory properties. We postulated that pre-treatment with MPLA would inhibit the inflammatory response of endothelial cells to secondary LPS challenge...
March 2016: Clinical Science (1979-)
Priscilla N Kelly, Donna L Romero, Yibin Yang, Arthur L Shaffer, Divya Chaudhary, Shaughnessy Robinson, Wenyan Miao, Lixin Rui, William F Westlin, Rosana Kapeller, Louis M Staudt
Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling...
December 14, 2015: Journal of Experimental Medicine
Seon-Young Han, Yean-Jung Choi, Min-Kyung Kang, Jung Han Yoon Park, Young-Hee Kang
A complicated interplay between resident mast cells and other recruited inflammatory cells contributes to the development and progression of allergic inflammation entailing the promotion of T helper 2 (Th2) cytokine responses. The current study examined whether resveratrol suppressed the production of inflammatory Th2 cytokines in cultured rat basophilic leukemia RBL-2H3 cells. Cells pre-treated with resveratrol nontoxic at 1–25 μM were sensitized with anti-dinitrophenyl (anti-DNP), and subsequently stimulated by dinitrophenyl-human serum albumin (DNP–HSA) antigen...
2015: American Journal of Chinese Medicine
Nehal M Elsherbiny, Mohammed M H Al-Gayyar, Khaled H Abd El Galil
AIMS: Inflammation plays significant roles in developing diabetic nephropathy (DN). Adenosine, natural purine nucleoside, acts as potent endogenous anti-inflammatory agent. Extracellular adenosine usually disappears quickly due to rapid uptake into adjacent cells. In this regard; we investigated putative reno-protective effects of dipyridamole, nucleoside transport inhibitor, by exploring its anti-inflammatory mechanisms in-vivo and in-vitro. MAIN METHODS: Daily 6mg/kg/day dipyridamole was given to six-weeks streptozotocin-induced diabetic rats over two-week period in presence/absence of 10mg/kg/day CGS15943, potent non selective adenosine receptors antagonist...
December 15, 2015: Life Sciences
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