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IL 17 cytokines receptor and inhibitor

Gianfranco Caselli, Albino Bonazzi, Marco Lanza, Flora Ferrari, Daniele Maggioni, Cristian Ferioli, Roberto Giambelli, Eleonora Comi, Silvia Zerbi, Marco Perrella, Ornella Letari, Elena Di Luccio, Milena Colovic, Stefano Persiani, Tiziano Zanelli, Laura Mennuni, Tiziana Piepoli, Lucio Claudio Rovati
BACKGROUND: Prostaglandin E2 (PGE2 ) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively...
March 1, 2018: Arthritis Research & Therapy
Yan Liu, Xiao-Xiao Rui, Hui Shi, Yi-Hua Qiu, Yu-Ping Peng
BACKGROUND Norepinephrine (NE), a neurotransmitter released from the sympathetic nerves, has been shown to be involved in rheumatoid arthritis (RA). However, its role in the sympathetic nervous system in RA is divergent. Herein, we demonstrate that the sympathetic neurotransmitter NE exerts an anti-inflammatory effect in collagen-induced arthritis (CIA), a mouse model of RA, by inhibiting Th17 cell differentiation and function via β2-adrenergic receptor (β2-AR) signaling. MATERIAL AND METHODS CIA was prepared by intradermal injection of collagen type II in the tail base of DBA1/J mice...
February 27, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Emilie Laprevotte, Stéphanie Cochaud, Stanislas du Manoir, Marion Lapierre, Cécile Dejou, Marion Philippe, Jérome Giustiniani, Kathryn A Frewer, Andrew J Sanders, Wen G Jiang, Henri-Alexandre Michaud, Pierre-Emmanuel Colombo, Armand Bensussan, Gilles Alberici, Jérémy Bastid, Jean-François Eliaou, Nathalie Bonnefoy
Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast cancer. We thus focused on IL-17B role in breast cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents...
December 26, 2017: Oncotarget
Tonya S Orchard, Rebecca R Andridge, Lisa D Yee, Maryam B Lustberg
BACKGROUND: Modifiable lifestyle factors, such as diet quality, could reduce inflammation and improve quality of life (QOL) in breast cancer survivors, but data are inconclusive. OBJECTIVE: To determine whether diet quality, as measured by Healthy Eating Index-2010 (HEI-2010) score, is associated with inflammation, health status, or functional outcomes affecting QOL in survivors of early-stage breast cancer. DESIGN: This is a cross-sectional, secondary analysis of baseline data collected from breast cancer survivors after completion of primary therapy and before random assignment to a pilot nutritional intervention aimed at reducing side effects of aromatase inhibitor treatment...
December 9, 2017: Journal of the Academy of Nutrition and Dietetics
Polly Niravath, Bingshu Chen, Judy-Anne W Chapman, Sandeep K Agarwal, Robert L Welschhans, Tim Bongartz, Krishna R Kalari, Lois E Shepherd, John Bartlett, Kathleen Pritchard, Karen Gelmon, Susan G Hilsenbeck, Mothaffar F Rimawi, C Kent Osborne, Paul E Goss, James N Ingle
BACKGROUND: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA. PATIENTS AND METHODS: MA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation...
October 16, 2017: Clinical Breast Cancer
Mina Amin, Kavita Darji, Daniel J No, Tina Bhutani, Jashin J Wu
BACKGROUND: The development of biologic agents directed against distinct cytokines and receptors has advanced the therapeutic options available for psoriasis patients. Evidence from preclinical studies suggests that IL-17 may contribute to the pathogenesis of psoriasis. OBJECTIVE: The objective was to review the safety and efficacy profile for each IL-17 inhibitor by evaluating phase III clinical trial data. METHODS: We reviewed the results of phase III clinical trials for the IL-17 inhibitors secukinumab, ixekizumab, and brodalumab...
November 10, 2017: Journal of Dermatological Treatment
Satveer K Mahil, Marika Catapano, Paola Di Meglio, Nick Dand, Helena Ahlfors, Ian M Carr, Catherine H Smith, Richard C Trembath, Mark Peakman, John Wright, Francesca D Ciccarelli, Jonathan N Barker, Francesca Capon
Interleukin (IL)-36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies...
October 11, 2017: Science Translational Medicine
T Oiwa, T Honda, A Otsuka, K Kabashima
No abstract text is available yet for this article.
October 6, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
Anna Balato, Emanuele Scala, Nicola Balato, Giuseppina Caiazzo, Roberta Di Caprio, Giuseppe Monfrecola, Annunziata Raimondo, Serena Lembo, Fabio Ayala
Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors. Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target...
November 2017: Expert Opinion on Biological Therapy
Morad Zayoud, Victoria Marcu-Malina, Einav Vax, Jasmine Jacob-Hirsch, Galit Elad-Sfadia, Iris Barshack, Yoel Kloog, Itamar Goldstein
The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization...
2017: Frontiers in Immunology
Charles J Malemud
Matrix metalloproteinases (MMPs) are zinc-dependent enzymes. These enzymes play a critical role in the destruction of articular cartilage in rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and the spondyloarthropathies. MMP gene expression is upregulated in these synovial joint pathologies in response to elevated levels of proinflammatory cytokines and soluble mediators such as tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, IL-17, and interferon-γ. These molecules are capable of activating the mitogen-activated protein kinase and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways by binding the cytokine to their respective receptors on immune cells, macrophages, chondrocytes, synoviocytes, and osteocytes leading to increased synthesis of MMPs...
2017: Progress in Molecular Biology and Translational Science
Ágnes Kemény, Kata Csekő, István Szitter, Zoltán V Varga, Péter Bencsik, Krisztina Kiss, Róbert Halmosi, László Deres, Krisztián Erős, Anikó Perkecz, László Kereskai, Terézia László, Tamás Kiss, Péter Ferdinandy, Zsuzsanna Helyes
Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model...
October 2017: Environmental Pollution
Shunsuke Imai, Tomohiro Otsuka, Akira Naito, Masamitsu Shimazawa, Hideaki Hara
BACKGROUND: Diabetic macular edema (DME) is resulted from the retinal microvascular leakage that accompanies the breakdown of blood-retinal barrier. Triamcinolone acetonide (TA) is a therapeutic agent for DME, but since the detailed mechanism of action of TA is not known, part of its action was examined. METHODS: In vitro model to enhance the permeability of human retinal microvascular endothelial cells (HRMECs) was constructed by using DME-related cytokines such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β)...
2017: Current Neurovascular Research
Barbara Żyżyńska-Granica, Bartosz Trzaskowski, Szymon Niewieczerzał, Sławomir Filipek, Oliwia Zegrocka-Stendel, Małgorzata Dutkiewicz, Piotr Krzeczyński, Magdalena Kowalewska, Katarzyna Koziak
Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors...
August 18, 2017: European Journal of Medicinal Chemistry
Abid Khan, Thomas Southworth, Sally Worsley, Srividya Sriskantharajah, Augustin Amour, Edith M Hessel, Dave Singh
Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. Phosphatidylinositol-3-kinase delta (PI3Kδ) is involved in lymphocyte activation. We investigated the effect of PI3Kδ inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein (rS6) as a potential biomarker of PI3Kδ activation. Peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells isolated from healthy never smokers (HNS), smokers (S) and COPD patients were stimulated to induce a T cell receptor response...
September 2017: Clinical and Experimental Pharmacology & Physiology
Maria G Ledesma-Colunga, Norma Adán, Georgina Ortiz, Mariana Solís-Gutiérrez, Fernando López-Barrera, Gonzalo Martínez de la Escalera, Carmen Clapp
BACKGROUND: Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA). METHODS: Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor...
May 15, 2017: Arthritis Research & Therapy
Seung-Heon Shin, Yee-Hyuk Kim, Mi-Kyung Ye, Sung-Yong Choi
BACKGROUND: Chronic rhinosinusitis with nasal polyps (NP) (CRSwNP) is classified into eosinophilic and noneosinophilic types based on the level of tissue eosinophilia. The immunopathologic features of Western and Asian CRSwNP differ. OBJECTIVES: The aim of this study was to investigate the immunopathologic characteristics of Korean patients with eosinophilic NP versus noneosinophilic NP and those with atopic NP versus nonatopic NP. METHODS: Tissue samples were collected from 81 patients with NP and 24 controls...
May 1, 2017: American Journal of Rhinology & Allergy
Philip Cohen, Sam Strickson
The adaptor protein MyD88 is required for signal transmission by toll-like receptors and receptors of the interleukin-1 family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex...
July 2017: Cell Death and Differentiation
Yong Zhang, Yanyan Zhang, Hao Li, Xiao Jia, Xiuying Zhang, Yan Xia, YuZhong Wang, Linlin Fu, Chenghua Xiao, Deqin Geng
OBJECTIVES: P2X7R is a well-documented activator of innate and adaptive immune responses. We aimed to measure the expression levels of P2X7R in peripheral blood mononuclear cells (PBMCs) from patients with myasthenia gravis (MG) and to investigate whether the expression of P2X7R is associated with pathogenesis of MG. PATIENTS AND METHODS: A total of 32 patients with MG (12 generalized MG (GMG) and 20 Ocular MG (OMG) and 22 healthy donors were recruited in this study...
June 2017: Clinical Neurology and Neurosurgery
Wan-Fu Wu, Laure Maneix, Jose Insunza, Ivan Nalvarte, Per Antonson, Juha Kere, Nancy Yiu-Lin Yu, Virpi Tohonen, Shintaro Katayama, Elisabet Einarsdottir, Kaarel Krjutskov, Yu-Bing Dai, Bo Huang, Wen Su, Margaret Warner, Jan-Åke Gustafsson
As estrogen receptor β-/- (ERβ-/- ) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERβ-/- mice and their WT littermates. We also treated young and old WT mice with an ERβ-selective agonist and evaluated protein expression. The most significant findings were that ERβ down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN)...
May 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
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