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Johnathan Ho, Christin Pelzel, Andreas Begitt, Maureen Mee, Hany M Elsheikha, David J Scott, Uwe Vinkemeier
STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27...
October 2016: PLoS Biology
Paulina Płoszaj, Andrzej Regiec, Stanisław Ryng, Agnieszka Piwowar, Marian L Kruzel
The 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide (HIX) is a synthetic isoxazole derivative with a potential for development as an anti-inflammatory drug candidate. The goal of this study was to explore in vitro autoimmune and inflammatory gene modulation by HIX in human Caco-2 cultured cells. The effect of low dose of HIX was tested on the expression level of RNA in 24h Caco-2 cultures using the QIAGEN Th17 for Autoimmunity & Inflammation RT(2) Profiler PCR Array. We choose the PCR technology as the most reliable and sensitive gene expression profiling method for analyzing specific gene regulatory networks...
October 17, 2016: Immunopharmacology and Immunotoxicology
Qinghong Wang, Jianguo Liu
IL-27 is a pleiotropic cytokine that has diverse immune regulatory activities under both physiological and pathological conditions. IL-27 enhances the functions of Th1 and CD8(+) T cells, promotes the development of Tfh and Tr1, and suppresses the functions of Th2, Treg, Th9, and Th17 cells. IL-27 is also involved in regulation of immune responses of B cells, NK, DCs, and macrophages. IL-27 production is strictly regulated at both transcriptional and posttranscriptional levels. Given its broad effects on immune regulation, IL-27 has been implicated in the pathogeneses of autoimmune and infectious diseases as well as cancers...
2016: Advances in Experimental Medicine and Biology
Sheikh Fayaz Ahmad, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M A Zoheir, Saleh A Bakheet, Abdulaziz M S Alsaad, Othman A Al-Shabanah, Sabry M Attia
We set out to investigate the influence of STA-21, a dynamic STAT-3 inhibitor, on the expansion and progression of rheumatoid arthritis (RA), and to determine its potential mechanisms of action in a mouse model of collagen antibody-induced arthritis (CAIA). To this end, arthritis was induced via intravenous (IV) injection of Balb/c mice with a cocktail of antibodies directed against type II collagen (1.5μg/mouse, IV), followed by lipopolysaccharide (LPS) at a dose of (25μg/mouse, i.p.) on day 3. Mice were then left untreated or were simultaneously treated with STA-21 (0...
October 3, 2016: Immunobiology
Carine Savarin, Cornelia C Bergmann, David R Hinton, Stephen A Stohlman
Viral infections have long been implicated as triggers of autoimmune diseases, including multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disorder. Epitope spreading, molecular mimicry, cryptic antigen, and bystander activation have been implicated as mechanisms responsible for activating self-reactive (SR) immune cells, ultimately leading to organ-specific autoimmune disease. Taking advantage of coronavirus JHM strain of mouse hepatitis virus (JHMV)-induced demyelination, this study demonstrates that the host also mounts counteractive measures to specifically limit expansion of endogenous SR T cells...
2016: Frontiers in Immunology
Li Jiang, Shuyu Yao, Su Huang, Jeffrey Wright, Thomas J Braciale, Jie Sun
Recent evidence has suggested that IL-10-producing effector CD8(+) T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8(+) T cells are not completely defined. Here we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8(+) T cells during influenza virus infection in mice. We find that type I IFNs can enhance IL-27 production by lung antigen presenting cells, thereby facilitating IL-10-producing CD8(+) T-cell development through a CD8(+) T cell non-autonomous way...
October 4, 2016: European Journal of Immunology
Xiaoqiong Su, Jue Pan, Fengxi Bai, Honglei Yuan, Nian Dong, Dandan Li, Xiangdong Wang, Zhihong Chen
BACKGROUND: Asthma is prone to Th2-mediated chronic airway inflammation. Interleukin-27 (IL-27) is a member of the IL-12 family that promotes the differentiation of Th1 cells and inhibits Th2 cells. We use human/mouse CD4(+) T cells to see whether IL-27 could inhibit IL-4 production in vitro and then observe whether IL-27 administration could alleviate allergic airway inflammation in vivo by mice asthma model. METHODS: We isolated and cultured CD4(+) T cells from healthy humans and mice to test whether IL-27 could inhibit IL-4 production under different conditions...
September 29, 2016: Journal of Translational Medicine
Andrea Petretto, Grazia Carbotti, Elvira Inglese, Chiara Lavarello, Maria Pia Pistillo, Valentina Rigo, Michela Croce, Luca Longo, Stefania Martini, Paola Vacca, Silvano Ferrini, Marina Fabbi
IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells...
September 24, 2016: Oncotarget
Frédérique Larousserie, Laura Bsiri, Valérie Dumaine, Céline Dietrich, Anne Audebourg, Brigitte Radenen-Bussière, Philippe Anract, Marie-Cécile Vacher-Lavenu, Odile Devergne
IL-27 regulates immune responses as well as hematopoiesis and bone remodeling, but its cellular sources in the bone remain unknown. In this study, we investigated whether osteoclasts and osteoblasts-the 2 cell types orchestrating bone homeostasis-could be a source of IL-27 and identified stimuli that induce its expression in vitro. We observed that human monocyte-derived osteoclasts expressed a broader range of TLRs than did human primary osteoblasts and that both cell types exhibited a differential induction of IL-27 expression in response to TLR or cytokine stimulation...
September 27, 2016: Journal of Leukocyte Biology
Yu He, Wei Xia Du, Hong Yan Jiang, Qing Ai, Jinxing Feng, Zhengqiu Liu, Jia Lin Yu
BACKGROUND: Early onset sepsis (EOS) remains a major cause of mortality and morbidity in neonates, and traditional clinical markers effective for adults are less effective in these patients. This study aimed to assess the value of individual plasma biomarkers as well as biomarker combinations for predicting EOS in neonates. METHODS: This prospective study included 151 neonates with suspected EOS. Plasma levels of interleukin (IL)-27, IL-6, IL-8, tumor necrosis factor (TNF)-α, heat shock protein (HSP) 70, macrophage inflammatory protein (MIP)-1α, MIP-1β, granzyme B, and matrix metalloproteinase (MMP)-8 were measured through multiplex cytokine profiling and assessed along with C-reactive protein (CRP) and procalcitonin (PCT)...
September 19, 2016: Shock
Zhu Zhang, Bin Zhou, Kui Zhang, Yaping Song, Lin Zhang, Mingrong Xi
Ovarian cancer continues to be the most lethal gynecologic malignancy worldwide. IL-27 is a novel member of the IL-12 cytokine family. The aim of this study was to investigate the effects of IL-27 on the ovarian cystadenocarcinoma cell line SKOV3 and determine possible mechanisms underlying its effect. We stably transfected an IL-27 plasmid, empty vector, IL-27 shRNA or negative control into SKOV3 cells. Cell proliferative activity was evaluated using a WST-1 cell proliferation assay kit. Cell viability was quantified by measurements of lactate dehydrogenase release...
October 2016: Molecular Immunology
Christian Hundhausen, Alena Roth, Elizabeth Whalen, Janice Chen, Anya Schneider, S Alice Long, Shan Wei, Rebecca Rawlings, MacKenzie Kinsman, Stephen P Evanko, Thomas N Wight, Carla J Greenbaum, Karen Cerosaletti, Jane H Buckner
Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3...
September 14, 2016: Science Translational Medicine
Sènan M d'Almeida, Gilles Kauffenstein, Charlotte Roy, Laetitia Basset, Loukas Papargyris, Daniel Henrion, Véronique Catros, Norbert Ifrah, Philippe Descamps, Anne Croue, Pascale Jeannin, Marc Grégoire, Yves Delneste, Julie Tabiasco
Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment. In patients with ovarian cancer, their density is correlated with poor prognosis. Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor...
July 2016: Oncoimmunology
Zorica Stojić-Vukanić, Biljana Bufan, Ivan Pilipović, Ivana Vujnović, Mirjana Nacka-Aleksić, Raisa Petrović, Nevena Arsenović-Ranin, Gordana Leposavić
: There are little data on modulatory effects of estrogens on rat dendritic cell (DC) responses to inflammatory stimuli, and consequently their ability to activate and polarize CD4+ T lymphocyte-mediated immune responses. Splenic conventional DCs from young female Albino Oxford rats were activated in vitro with LPS (TLR4 agonist) or R848 (TLR7/8 agonist) in the presence and absence of 17β-estradiol (E2), and their allostimulatory and CD4+ lymphocyte polarizing ability in mixed leukocyte culture (MLC) were studied...
September 9, 2016: International Immunopharmacology
Dipti Vijayan, Norhanani Mohd Redzwan, Danielle T Avery, Rushika C Wirasinha, Robert Brink, Giles Walters, Stephen Adelstein, Masao Kobayashi, Paul Gray, Michael Elliott, Melanie Wong, Cecile King, Carola G Vinuesa, Nico Ghilardi, Cindy S Ma, Stuart G Tangye, Marcel Batten
Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20(+)CD38(+)CD27(low)CD95(+)CD10(+) cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3 To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquin(san/san) lupus mouse model...
September 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Outi Heikkilä, Michaela Nygårdas, Henrik Paavilainen, Elina Ryödi, Veijo Hukkanen
Interleukin-27 (IL-27) inhibits the replication of many viruses, but the mechanism differs according to virus and cell type. In this study, we observed that IL-27 expression was upregulated in herpes simplex virus type 1 (HSV-1)-infected SJL/J mice, which led us to further investigate the role of IL-27 in HSV-1 infection using epithelial, glioma, and immunological cells as cell models. We showed that in all studied cell lines, the IL-27 messenger RNA (mRNA) level was upregulated due to the HSV-1 infection. When the cells were primed with IL-27 before the virus infection, the virus release was prevented, indicating an antiviral role of IL-27 in HSV-1 infection...
September 12, 2016: Journal of Interferon & Cytokine Research
Rasoul Baharlou, Abbas Ahmadi-Vasmehjani, Mohammad Hasan Davami, Fatemeh Faraji, Mohammd Reza Atashzar, Firoozeh Karimipour, Alireza Sadeghi, Mohammad-Ali Asadi, Mahshid Khoubyari
BACKGROUND: Type 1 diabetes (T1D) is thought to involve chronic inflammation, which is manifested by the activation and expression of different inflammatory mediators. Th1- and Th17-associated cytokines are factors that have been shown to exert profound pro-inflammatory activities and have been implicated in the pathogenesis of T1D in mice and humans. OBJECTIVES: Therefore, the aim of this case control study was to determine the serum level of IL-17, IL-21, IL-27, transforming growth factor beta (TGF-β), and IFN-γ and their reciprocal relationship in Iranian T1D patients...
October 2016: Immunological Investigations
Yazhong Tao, Xin Zhang, Silva Markovic-Plese
We report that B cells from patients with RRMS have decreased endogenous IFN-β secretion and deficient IFN receptor (IFNAR)1/2 and TLR7 gene expression in comparison to healthy controls (HCs), which may contribute to disregulation of cytokine secretion by B cells. We propose that TLR7 and TLR9 stimulation with loxorubin (LOX) and CpG, in combination with exogenous IFN-β may effectively reconstitute endogenous IFN-β production deficit and induce the secretion of immunoregulatory cytokines by B cells. Both LOX/IFN-β and CpG/IFN-β in-vitro treatments of B cells from RRMS patients induced higher endogenous IFN-β gene expression in comparison to the exogenous IFN-β alone...
September 15, 2016: Journal of Neuroimmunology
Yuko Ujiie, Takeo Karakida, Yasuo Yamakoshi, Tomoko Ohshima, Kazuhiro Gomi, Shinichiro Oida
OBJECTIVE: Human gingival epithelium is continuously exposed to bacteria and acts as the first line of defense in periodontal tissues. It is crucial to maintain healthy, non-inflamed gingival tissue to avoid gingivitis and periodontitis. The purpose of this study was to investigate the influence of IL-4 in human gingival fibroblasts (hGF) on the activation of osteoclasts. DESIGN: Two hGF samples were obtained from two healthy patients, and one was collected from a commercially available resource...
August 28, 2016: Archives of Oral Biology
Zhihong Chen, Jue Pan, Yi Jia, Dandan Li, Zhihui Min, Xiaoqiong Su, Honglei Yuan, Geng Shen, Shengxuan Cao, Lei Zhu, Xiangdong Wang
BACKGROUND: Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown. METHODS: Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study...
August 31, 2016: Cell Biology and Toxicology
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