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Yu Hui Kang, Amlan Biswas, Michael Field, Scott B Snapper
The JAK-STAT pathway critically regulates T-cell differentiation, and STAT1 is postulated to regulate several immune-mediated diseases by inducing proinflammatory subsets. Here we show that STAT1 enables CD4+ T-cell-mediated intestinal inflammation by protecting them from natural killer (NK) cell-mediated elimination. Stat1-/- T cells fail to expand and establish colitis in lymphopenic mice. This defect is not fully recapitulated by the combinatorial loss of type I and II IFN signaling. Mechanistically, Stat1-/- T cells have reduced expression of Nlrc5 and multiple MHC class I molecules that serve to protect cells from NK cell-mediated killing...
February 22, 2019: Nature Communications
Valentina Martin, Cristina Chiriaco, Chiara Modica, Anna Acquadro, Marco Cortese, Francesco Galimi, Timothy Perera, Loretta Gammaitoni, Massimo Aglietta, Paolo M Comoglio, Elisa Vigna, Dario Sangiolo
BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours. METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy...
February 6, 2019: British Journal of Cancer
H A Drexhage
In this issue of BBI Melbourne et al describe a reduced activity of the JAK-STAT1 pathway in leukocytes of early and acute schizophrenia patients. This editorial discusses the report of Melbourne et al as being in accord with the view that active forms of schizophrenia are characterized by a de-activation of the Th1 driven M1/JAK-STAT1 mediated pro-inflammatory pathway in myeloid cells (macrophages, dendritic cells and microglia). Myeloid cells can be inflammatory activated and de-activated via various different molecular pathways (leading to various types of macrophages, such as e...
January 22, 2019: Brain, Behavior, and Immunity
Jennifer K Melbourne, Cherise Rosen, Benjamin Feiner, Yanzhen Pang, Rajiv P Sharma
Multiple lines of inquiry demonstrate alterations to immune function in psychosis. Clinically, this is reflected by elevated proinflammatory cytokines in serum, indicating activation of circulating immune cells. Data from isolated cells in clinical populations support the presence of altered activity of pertinent intracellular signaling pathways. Here, we focus on the well-characterized IFN-γ mediated JAK-STAT1 signaling pathway, which is involved in multiple aspects of immunity, including activation of circulating immune cells to a proinflammatory phenotype...
November 29, 2018: Brain, Behavior, and Immunity
Manyuan Xu, Zhongsheng Min, Yuegang Wei
Objective To detect the effect of glycyrrhizin (GL) on the expression of CXCL10 induced by IFN-γ in HaCaT cells. Methods HaCaT cells were cultured in vitro. IFN-γ at the dosage of 10 ng/mL was used to establish the model group. GL (0.5 mmol/L), JAK1/2 inhibitor CYT387 (15 nmol/L), and combined therapy of GL and CYT387 were administrated in IFN-γ-treated HaCaT cells, respectively. Cell viability was detected by MTT assay. The expression of CXCL10 was assessed via real-time quantitative PCR and ELISA. Protein phosphorylation of the JAK1/2 and STAT1 was determined using western blot analysis...
August 2018: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Yong Shen, Saisai Wang, Fangfang Sun, Gang Zheng, Tingting Wu, Yushen Du, Suzhan Zhang, Jing Qian, Ren Sun
Gamma interferon (IFN-γ) is known to negatively regulate murine gammaherpesvirus-68 (MHV-68 or γHV-68) replication. This process involves the suppression of the viral gene replication and transcription activator (RTA) promoter, as well as activation of signal transducers and activators of transcription (STAT1). Notably, this effect is gradually attenuated during MHV-68 infection of bone marrow-derived macrophages (BMMs), which raised the possibility that the virus may utilize a mechanism that counteracts the antiviral effect of IFN-γ...
August 2018: PLoS Pathogens
Eun J Park, Young M Kim, Hye J Kim, Ki C Chang
High mobility group box 1 (HMGB1) has been proposed as crucial in the pathogenesis of many diseases including sepsis. Acetylation of HMGB1 prevents its entry into the nucleus and leads to its secretion from the cell where it can trigger inflammation. We hypothesized that histone deacetylase 4 (HDAC4) controls the acetylation of HMGB1 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The results showed that LPS treatment promoted the degradation of HDAC4 in a proteasome-dependent manner, which led to HMGB1 acetylation...
July 2018: FEBS Open Bio
Antoine Dufour, Caroline L Bellac, Ulrich Eckhard, Nestor Solis, Theo Klein, Reinhild Kappelhoff, Nikolaus Fortelny, Parker Jobin, Jacob Rozmus, Jennifer Mark, Paul Pavlidis, Vincent Dive, Sean J Barbour, Christopher M Overall
Controlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show a negative feedback mechanism for proinflammatory IFN-γ activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-γ at 135Glu↓Leu136 the IFN-γ receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-γ activation of proinflammatory macrophages...
June 20, 2018: Nature Communications
Edit Porpaczy, Sabrina Tripolt, Andrea Hoelbl-Kovacic, Bettina Gisslinger, Zsuzsanna Bago-Horvath, Emilio Casanova-Hevia, Emmanuelle Clappier, Thomas Decker, Sabine Fajmann, Daniela A Fux, Georg Greiner, Sinan Gueltekin, Gerwin Heller, Harald Herkner, Gregor Hoermann, Jean-Jacques Kiladjian, Thomas Kolbe, Christoph Kornauth, Maria-Theresa Krauth, Robert Kralovics, Leonhard Muellauer, Mathias Mueller, Michaela Prchal-Murphy, Eva Maria Putz, Emmanuel Raffoux, Ana-Iris Schiefer, Klaus Schmetterer, Christine Schneckenleithner, Ingrid Simonitsch-Klupp, Cathrin Skrabs, Wolfgang R Sperr, Philipp Bernhard Staber, Birgit Strobl, Peter Valent, Ulrich Jaeger, Heinz Gisslinger, Veronika Sexl
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk)...
August 16, 2018: Blood
Keiko Aota, Koichi Kani, Tomoko Yamanoi, Koh-Ichi Nakashiro, Naozumi Ishimaru, Masayuki Azuma
CXCL10, a CXC chemokine induced by interferon-gamma [IFN-γ], has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions. Although CXCL10 is known to be overexpressed in the salivary glands of individuals with primary Sjögren's syndrome (pSS), it is unclear which cells produce CXCL10 under what types of stimulations. Here, we investigated the precise molecular mechanisms by which CXCL10 was produced in human salivary gland ductal (NS-SV-DC) and acinar (NS-SV-AC) cell lines...
August 2018: Inflammation
Jennifer K Melbourne, Cherise Rosen, Benjamin Feiner, Rajiv P Sharma
Altered immune function is an established finding in psychotic disorders such as schizophrenia and bipolar disorder with psychosis, though its role in their development and progression remains to be understood. Evidence suggests altered JAK-STAT1 pathway activity in peripheral blood cells from participants with schizophrenia compared to controls. Activation of this pathway leads to increased expression of complement component 4A (C4A), which has recently been implicated in schizophrenia. Here, we examine mRNA expression of C4A in peripheral blood cells from participants with schizophrenia, bipolar disorder and controls...
February 12, 2018: Schizophrenia Research
Dae Seong Kim, In Keun Jang, Myoung Woo Lee, Young Jong Ko, Doo-Hoon Lee, Ji Won Lee, Ki Woong Sung, Hong Hoe Koo, Keon Hee Yoo
Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases owing to their immunosuppressive properties. In this study, we aimed to identify the effect of interferon (IFN)-γ priming on immunomodulation by MSCs and elucidate the possible mechanism underlying their properties for the clinical treatment of allogeneic conflicts. Infusion of MSCs primed with IFN-γ significantly reduced the symptoms of graft-versus-host disease (GVHD) in NOD-SCID mice, thereby increasing survival rate when compared with naïve MSC-infused mice...
February 2018: EBioMedicine
Jin Wei, Wei Guo, Huan Lian, Qing Yang, Heng Lin, Shu Li, Hong-Bing Shu
IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKβ-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Na Li, Jianing Wang, Na Zhang, Mengwei Zhuang, Zhaoyun Zong, Jiahuan Zou, Guosheng Li, Xiaoyan Wang, Huaiyu Zhou, Lining Zhang, Yongyu Shi
Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC...
February 2018: Cancer Immunology, Immunotherapy: CII
R Krishnan Kutty, William Samuel, Todd Duncan, Olga Postnikova, Cynthia Jaworski, Chandrasekharam N Nagineni, T Michael Redmond
The inflammatory response may contribute to retinal pigment epithelial (RPE) dysfunction associated with the pathogenesis of age-related macular degeneration (AMD). We investigated whether the inflammatory response affects the expression of long coding RNAs (lncRNAs) in human RPE-derived ARPE-19 cells. This class of regulatory RNA molecules recently came to prominence due to their involvement in many pathophysiological processes. A proinflammatory cytokine mixture consisting of IFN-γ, IL-1β and TNF-α altered the expression several lncRNAs including BANCR in these cells...
April 2018: Cytokine
Cathleen Reiber, Anne Brieger, Gabriela Engelhardt, Silke Hebel, Lothar Rink, Hajo Haase
One consequence of lipopolysaccharide (LPS)-induced stimulation of macrophages is the release of Interferon (IFN)-β, and subsequently the activation of the JAK-STAT1 pathway, resulting in the expression of inducible nitric oxide synthase (iNOS). Free intracellular zinc ions (Zn2+ ) have a profound impact as a second messenger in LPS-dependent gene expression. Previous work had indicated a Zn2+ -dependent upregulation of STAT1 mRNA in response to LPS and IFN-β, potentially affecting STAT1-dependent downstream signaling upon pre-incubation with these agents...
December 2017: Journal of Trace Elements in Medicine and Biology
Shimei Qi, Zunyong Feng, Qiang Li, Zhilin Qi, Yao Zhang
Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin's effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS...
2017: Oxidative Medicine and Cellular Longevity
Satish K Noonepalle, Franklin Gu, Eun-Joon Lee, Jeong-Hyeon Choi, Qimei Han, Jaejik Kim, Maria Ouzounova, Austin Y Shull, Lirong Pei, Pei-Yin Hsu, Ravindra Kolhe, Fang Shi, Jiseok Choi, Katie Chiou, Tim H M Huang, Hasan Korkaya, Libin Deng, Hong-Bo Xin, Shuang Huang, Muthusamy Thangaraju, Arun Sreekumar, Stefan Ambs, Shou-Ching Tang, David H Munn, Huidong Shi
Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells...
April 2017: Cancer Immunology Research
Abul Azad, Su Yin Lim, Zenobia D'Costa, Keaton Jones, Angela Diana, Owen J Sansom, Philipp Kruger, Stanley Liu, W Gillies McKenna, Omer Dushek, Ruth J Muschel, Emmanouil Fokas
Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts...
February 2017: EMBO Molecular Medicine
Mathias Schneider, Thomas Efferth, Heba Abdel-Aziz
Inflammatory bowel diseases (IBD) are chronic relapsing intestinal disorders characterized by up-regulation of pro-inflammatory cytokines followed by invasion of immune cells to the intestinal lamina propria. Standard therapies consist of anti-inflammatory or immunosuppressive drugs. Since clinical efficiency is not satisfactory and the established drugs have massive side effects, new strategies to treat IBD are required. Herein, we investigate the protective effect of the fixed combination herbal preparations STW5 and STW5-II and the contribution of the corresponding single components in an in vitro inflammation model...
2016: Frontiers in Pharmacology
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