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IL 17 cytokines receptor and inhibitor

Samuel Hintermann, Christine Guntermann, Henri Mattes, David A Carcache, Juergen Wagner, Anna Vulpetti, Andreas Billich, Janet Dawson, Klemens Kaupmann, Joerg Kallen, Rowan Stringer, David Orain
Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed...
November 30, 2016: ChemMedChem
Thomas Southworth, Jonathan Plumb, Vandana Gupta, James Pearson, Isabel Ramis, Martin D Lehner, Montserrat Miralpeix, Dave Singh
BACKGROUND: Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression. METHOD: Cells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation...
October 4, 2016: Respiratory Research
Agnieszka Wasilewska, Marta Winiarska, Małgorzata Olszewska, Lidia Rudnicka
Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment - a fully human monoclonal antibody that targets IL-17A (secukinumab)...
August 2016: Postȩpy Dermatologii i Alergologii
D M Saunte, U Mrowietz, L Puig, C Zachariae
The recognition of the central role of interleukin 17A (IL-17A) in the pathogenesis of psoriasis has led to the development of several monoclonal antibodies targeting this cytokine or its receptors for therapeutic purposes. IL-17A also plays an important role in the immunological protection against infections, especially those due to Candida sp., as evidenced by findings in patients with genetic defects in IL-17 related immune responses. To assess the potential of anti-Il-17 treatment to promote Candida infections, here we have systematically reviewed published clinical trials of patients with psoriasis or psoriatic arthritis...
August 31, 2016: British Journal of Dermatology
Huilong Chen, Xiangqin Xu, Jieming Teng, Sheng Cheng, Hansvin Bunjhoo, Yong Cao, Jin Liu, Jungang Xie, Congyi Wang, Yongjian Xu, Weining Xiong
Accumulating evidence suggests that chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) may contribute to the pathogenesis of allergic asthma. However, the underlying molecular mechanisms remain to be fully understood. T-helper 17 cells (Th17) and T-cytotoxic 17 cells (Tc17) have been implicated in the development of several allergic disorders, including asthma. The present study aimed to explore the association between CXCL12 signaling and Th17/Tc17 cells in the development of asthma...
May 2016: Experimental and Therapeutic Medicine
Qingli Bie, Caixia Sun, Aihua Gong, Chunye Li, Zhaoliang Su, Dong Zheng, Xiaoyun Ji, Yumin Wu, Qi Guo, Shengjun Wang, Huaxi Xu
Inflammation is a critical component involved in tumor progression. Interleukin-17 (IL-17) belongs to a relatively new family of cytokines that has been associated with the progression of cancers. However, the role of IL-17B/IL-17RB (IL-17 receptor B) signaling to stemness of gastric cancer remains unknown. Here, we confirmed that the expression of IL-17RB in gastric cancer tissues was significantly increased, that overexpression was associated with poor prognosis of gastric cancer patients, and that overexpression was positively correlated with some stemness markers...
2016: Scientific Reports
Benjamin Luchting, Jens Heyn, Tobias Woehrle, Banafscheh Rachinger-Adam, Simone Kreth, Ludwig C Hinske, Shahnaz C Azad
BACKGROUND: Despite substantial progress, pathogenesis and therapy of chronic pain are still the focus of many investigations. The ATP-gated P2X7 receptor (P2X7R) has previously been shown to play a central role in animal models of nociceptive inflammatory and neuropathic pain. Recently, we found that the adaptive immune system is involved in the pathophysiology of chronic nociceptive and neuropathic pain in humans. So far, data regarding P2X7R expression patterns on cells of the adaptive immune system of pain patients are scarce...
2016: Journal of Neuroinflammation
Zhaoyang Chen, Min Guo, Guohua Song, Jiping Gao, Yinhong Zhang, Zhijie Jing, Tianfu Liu, Chuan Dong
Schisandrin B (Sch-B), the most abundant active ingredient of the fruit of Schisandra chinensis, has been proposed to have antioxidant, anti-tumor and anti-inflammatory effects. The present study was undertaken to investigate the effect of Sch-B on differentiation of T helper cells (Th). Using mouse splenic lymphocytes stimulated with concanavalin A (Con A) in vitro and ex vivo as inflammation models, we found that Sch-B significantly inhibited secretion of Th1 and Th17 related cytokines, such as IFN-γ and IL-17...
June 2016: International Immunopharmacology
Adèle de Masson, Jean-David Bouaziz, Maxime Battistella, Martine Bagot, Armand Bensussan
Psoriasis is a frequent inflammatory disease that involves mostly the skin and sometimes the joints. This chronic disease is rarely life-threatening but impairs significantly the patient's quality of life. It is characterized, in its typical form, by erythematous and squamous plaques with well-defined borders, associated with increased proliferation of the keratinocytes, inflammation and greater number of dilated blood vessels in the upper dermis. A role of Th1 CD4 T cells was initially suspected. More recently, Th17 CD4 T cells have been shown to play a major role in the disease...
March 2016: Médecine Sciences: M/S
Jürgen Braun, Xenofon Baraliakos, Uta Kiltz
INTRODUCTION: Ankylosing spondylitis (AS) is a chronic immune-mediated disease characterised by inflammation and new bone formation in the axial skeleton. Current therapeutic strategies include non-steroidal anti-inflammatory drugs, local glucocorticoids and tumour necrosis factor inhibitors. However, an unmet need exists for more treatment options particularly for patients who become unresponsive to and/or cannot tolerate these medications. Interleukin (IL)-17A, a proinflammatory cytokine that plays a crucial role in the pathogenesis of AS, has emerged as a promising target in the search for new therapies...
2016: Expert Opinion on Biological Therapy
A I Konoplya, V B Laskov, A A Shul'ginova
OBJECTIVE: To determine the dynamics of immunometabolic characteristics in patients with chronic ischemia of the brain (discirculatory encephalopathy - DE) under the influence of various combinations of neuroprotective and antioxidant drugs and on this basis to identify the most effective therapeutic combinations. MATERIAL AND METHODS: Authors analyzed the results of treatment of 57 patients with DE, stage II, comorbid to hypertension, stage II, which were divided into 3 groups that received comprehensive basic and advanced therapy with paired combinations of neuroprotective and antioxidant drugs...
2015: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Sphoorthi Jinna, Bruce Strober
Psoriasis is a chronic, immune-mediated, inflammatory dermatosis, affecting 2-3% of the US population. While first-generation cytokine antagonists targeting tumor necrosis factor alpha (TNF-α)-dependent pathways have produced favorable responses in the treatment of psoriasis, higher levels of efficacy in a greater proportion of patients have been shown in trials with antibodies targeting interleukin (IL)-17A and the IL-17 receptor subunit. This examines the role of IL-17 inhibitors in the treatment of plaque psoriasis...
August 2016: Journal of Dermatological Treatment
Takuma Sakurai, Daigo Yoshiga, Wataru Ariyoshi, Toshinori Okinaga, Hiroyasu Kiyomiya, Junya Furuta, Izumi Yoshioka, Kazuhiro Tominaga, Tatsuji Nishihara
BACKGROUND: The tumor cells were needed to rearrange the extracellular matrix (ECM) and reorganize their cytoskeleton to facilitate the cell motility during the tumor invasion. The proinflammatory cytokine interleukin-17A (IL-17A) is reported to up-regulate tumor invasiveness via ECM degradation by matrix metalloproteinases (MMPs). However the precise effects of IL-17A-dependent invasion remain to be characterized. The aim of this study was to elucidate the mechanisms underlying IL-17A-induced MMP-3 expression in the human synovial sarcoma cells HS-SY-II...
2016: BMC Research Notes
Toshio Hattori, Naomi Ogura, Miwa Akutsu, Mutsumi Kawashima, Suguru Watanabe, Ko Ito, Toshirou Kondoh
Synovial fibroblasts contribute to the inflammatory temporomandibular joint under pathogenic stimuli. Synovial fibroblasts and T cells participate in the perpetuation of joint inflammation in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. IL-17 is an inflammatory cytokine produced primarily by Th17 cells which plays critical role in the pathogenesis of numerous autoimmune and inflammatory diseases. Here, we investigated the roles of IL-17A in temporomandibular joint disorders (TMD) using genome-wide analysis of synovial fibroblasts isolated from patients with TMD...
2015: Mediators of Inflammation
Audrey Beringer, Melissa Noack, Pierre Miossec
Interleukin-17 (IL-17) is a cytokine which elicits protection against extracellular bacterial and fungal infections and which plays important roles in inflammation. However, when produced in excess, it contributes to chronic inflammation associated with many inflammatory and autoimmune disorders. This has made IL-17 an attractive therapeutic target. The present review describes the structure of the IL-17 family, the IL-17 receptor complex, and the cells producing IL-17. The contributions of IL-17 to disease as well as new IL-17-based treatment options are discussed...
March 2016: Trends in Molecular Medicine
Jezrom B Fordham, Afsar R Naqvi, Salvador Nares
OBJECTIVE: MicroRNAs (miRNA) are ubiquitous regulators of human biology and immunity. Previously, we have demonstrated an inhibitory role for miR-24 in the phagocytosis of Escherichia coli and Staphylococcus aureus bioparticles and the induction of cytokine secretion in response to lipopolysaccharide (LPS) of the same origin; also, we have identified divergent and convergent miRNA responses to LPS from the periodontopathic pathogens Aggregatibacter actinomycetemcomitams (Aa) and Porphyromonas gingivalis (Pg), and revealed cigarette smoke extract as an environmental modifier of Pg LPS structure (Pg CSE) impacting macrophage miRNA responses...
October 2015: Journal of Clinical & Cellular Immunology
Hui Lin, Pingfang Song, Yi Zhao, Li-Jia Xue, Yi Liu, Cong-Qiu Chu
T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease...
2015: Mediators of Inflammation
Andreas Willerslev-Olsen, Thorbjørn Krejsgaard, Lise M Lindahl, Ivan V Litvinov, Simon Fredholm, David L Petersen, Claudia Nastasi, Robert Gniadecki, Nigel P Mongan, Denis Sasseville, Mariusz A Wasik, Charlotte M Bonefeld, Carsten Geisler, Anders Woetmann, Lars Iversen, Mogens Kilian, Sergei B Koralov, Niels Odum
Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells...
March 10, 2016: Blood
Tapas K Makar, Volodymyr Gerzanich, Vamshi K C Nimmagadda, Rupal Jain, Kristal Lam, Fahad Mubariz, David Trisler, Svetlana Ivanova, Seung Kyoon Woo, Min Seong Kwon, Joseph Bryan, Christopher T Bever, J Marc Simard
BACKGROUND: In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression...
November 18, 2015: Journal of Neuroinflammation
Angelo V Marzano, Simona Tavecchio, Emilio Berti, Carlo Gelmetti, Massimo Cugno
The therapy of inflammatory bowel disease, particularly with tumor necrosis factor (TNF) blockers, may be associated with a number of cutaneous adverse effects, including psoriasis-like, eczema-like, and lichenoid eruptions. Other rare skin complications are neutrophilic dermatoses such as amicrobial pustulosis of the folds (APF), which is a chronic relapsing pustular disorder classified in this spectrum.The authors analyzed clinical, histopathologic, and cytokine expression profiles of 3 inflammatory bowel disease patients with APF triggered by adalimumab (patient 1) and infliximab (patients 2 and 3)...
November 2015: Medicine (Baltimore)
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