Journal articles: 'Interferon Regulator Faktor 1'

1

Xu, Xiao, Keli Chai, Yuhang Chen, Yongquan Lin, Suzhen Zhang, Xin Li, Wentao Qiao, and Juan Tan. "Interferon activates promoter of Nmi gene via interferon regulator factor-1." Molecular and Cellular Biochemistry 441, no. 1-2 (September 14, 2017): 165–71. http://dx.doi.org/10.1007/s11010-017-3182-y.

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2

Yan, Rui, Matijs van Meurs, Eliane R. Popa, Rianne M. Jongman, Peter J. Zwiers, Anita E. Niemarkt, Timara Kuiper, et al. "Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB." Journal of Innate Immunity 9, no. 6 (2017): 546–60. http://dx.doi.org/10.1159/000477211.

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Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-α-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF-1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFκB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFκB.

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Hector, Andreas, Michael Kormann, Julia Kammermeier, Sofia Burdi, Veronica Marcos, Nikolaus Rieber, Lauren Mays, et al. "Expression and Regulation of Interferon-Related Development Regulator–1 in Cystic Fibrosis Neutrophils." American Journal of Respiratory Cell and Molecular Biology 48, no. 1 (January 2013): 71–77. http://dx.doi.org/10.1165/rcmb.2012-0061oc.

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Blanco, Jorge C. G., Cristina Contursi, Cindy A. Salkowski, David L. DeWitt, Keiko Ozato, and Stefanie N. Vogel. "Interferon Regulatory Factor (Irf)-1 and Irf-2 Regulate Interferon γ–Dependent Cyclooxygenase 2 Expression." Journal of Experimental Medicine 191, no. 12 (June 19, 2000): 2131–44. http://dx.doi.org/10.1084/jem.191.12.2131.

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Cyclooxygenases (Cox) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. Cox-2 is the inducible isoform that is upregulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. In this study, we demonstrate that interferon (IFN)-γ alone or in synergy with lipopolysaccharide (LPS) or interleukin 1α induces Cox-2 expression in mouse peritoneal macrophages, which is paralleled by changes in Cox-2 protein levels and prostaglandin E2 (PGE2) release. Induction of Cox-2 was abrogated in macrophages that lack IFN regulatory factor (IRF)-1, consistent with an attenuated hepatic mRNA response in IRF-1−/− mice injected with LPS. Conversely, the absence of IRF-2 in macrophages resulted in a significant increase in both basal and inducible Cox-2 gene and protein expression as well as IFN-γ–stimulated PGE2 release, identifying IRF-2 as negative regulator of this promoter. Two IFN stimulation response elements were identified in the mouse Cox-2 promoter that were highly conserved in the human Cox-2 gene. Both bind endogenous IRF-1 and IRF-2 and regulate transcription in an IRF-1/2–dependent manner. Our data demonstrate conclusively the importance of IFN-γ as a direct activator and coactivator of the Cox-2 gene, and the central role of IRF-1/2 family members in this process.

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Rubinstein, Yaffa R., Kimberle N. Proctor, Michael Bergel, Barbara Murphy, and Alfred C. Johnson. "Interferon regulatory factor-1 is a major regulator of epidermal growth factor receptor gene expression." FEBS Letters 431, no. 2 (July 17, 1998): 268–72. http://dx.doi.org/10.1016/s0014-5793(98)00774-1.

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6

Qian, Wei, Xiaoqin Wei, Yongtao Li, Kelei Guo, Zhong Zou, Hongbo Zhou, and Meilin Jin. "Duck interferon regulatory factor 1 acts as a positive regulator in duck innate antiviral response." Developmental & Comparative Immunology 78 (January 2018): 1–13. http://dx.doi.org/10.1016/j.dci.2017.09.004.

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7

Qi, Zhihong, Fang Wang, Guotao Yu, Di Wang, Yingpeng Yao, Menghao You, Jingjing Liu, et al. "SRSF1 serves as a critical posttranscriptional regulator at the late stage of thymocyte development." Science Advances 7, no. 16 (April 2021): eabf0753. http://dx.doi.org/10.1126/sciadv.abf0753.

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The underlying mechanisms of thymocyte maturation remain largely unknown. Here, we report that serine/arginine-rich splicing factor 1 (SRSF1) intrinsically regulates the late stage of thymocyte development. Conditional deletion of SRSF1 resulted in severe defects in maintenance of late thymocyte survival and a blockade of the transition of TCRβhiCD24+CD69+ immature to TCRβhiCD24−CD69− mature thymocytes, corresponding to a notable reduction of recent thymic emigrants and diminished periphery T cell pool. Mechanistically, SRSF1 regulates the gene networks involved in thymocyte differentiation, proliferation, apoptosis, and type I interferon signaling pathway to safeguard T cell intrathymic maturation. In particular, SRSF1 directly binds and regulates Irf7 and Il27ra expression via alternative splicing in response to type I interferon signaling. Moreover, forced expression of interferon regulatory factor 7 rectifies the defects in SRSF1-deficient thymocyte maturation via restoring expression of type I interferon–related genes. Thus, our work provides new insight on SRSF1-mediated posttranscriptional regulatory mechanism of thymocyte development.

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von Gamm, Matthias, Annalisa Schaub, Alisha N. Jones, Christine Wolf, Gesine Behrens, Johannes Lichti, Katharina Essig, et al. "Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3." Journal of Experimental Medicine 216, no. 7 (May 24, 2019): 1700–1723. http://dx.doi.org/10.1084/jem.20181762.

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The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed Regnase-3–deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell–specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade, and regulate mRNAs, such as Zc3h12a (Regnase-1), in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.

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9

Park, Hyun-Jung, Won-Young Lee, Ha-Yeon Jeong, Hee-Seol Kang, Jong-Bo Kim, and Hyuk Song. "Mitochondrial interferon-induced transmembrane protein-1 is a critical regulator of cell death in MPRO cells." Biotechnology and Bioprocess Engineering 21, no. 4 (August 2016): 561–66. http://dx.doi.org/10.1007/s12257-016-0253-y.

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10

Arockiaraj, Jesu, Sarasvathi Easwvaran, Puganeshwaran Vanaraja, Arun Singh, Rofina Yasmin Othman, and Subha Bhassu. "First report on interferon related developmental regulator-1 from Macrobrachium rosenbergii: Bioinformatic analysis and gene expression." Fish & Shellfish Immunology 32, no. 5 (May 2012): 929–33. http://dx.doi.org/10.1016/j.fsi.2012.02.011.

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11

Kim, Kyoung Min, Sajeev Wagle, Young Jae Moon, Sung Il Wang, Byung-Hyun Park, Kyu Yun Jang, and Jung Ryul Kim. "Interferon β protects against avascular osteonecrosis through interleukin 6 inhibition and silent information regulator transcript-1 upregulation." Oncotarget 9, no. 3 (December 16, 2017): 3562–75. http://dx.doi.org/10.18632/oncotarget.23337.

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12

Iezaki, Takashi, Yuki Onishi, Kakeru Ozaki, Kazuya Fukasawa, Yoshifumi Takahata, Yukari Nakamura, Koichi Fujikawa, et al. "The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption." Journal of Bone and Mineral Research 31, no. 3 (October 22, 2015): 573–84. http://dx.doi.org/10.1002/jbmr.2720.

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13

Marro, Brett S., Brian C. Ware, Jaroslav Zak, Juan Carlos de la Torre, Hugh Rosen, and Michael B. A. Oldstone. "Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling." Proceedings of the National Academy of Sciences 114, no. 14 (March 21, 2017): 3708–13. http://dx.doi.org/10.1073/pnas.1700878114.

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Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune “antiself” T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.

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14

Seo, Taegun, Daeyoup Lee, Young Sam Shim, Jon E. Angell, Natesa V. Chidambaram, Dhananjaya V. Kalvakolanu, and Joonho Choe. "Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death." Journal of Virology 76, no. 17 (September 1, 2002): 8797–807. http://dx.doi.org/10.1128/jvi.76.17.8797-8807.2002.

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ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) plays a significant role in the development of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. The KSHV open reading frame K9 encodes the viral interferon (IFN) factor 1 (vIRF1), which downregulates IFN- and IRF-mediated transcriptional activation, and leads to cellular transformation in rodent fibroblasts and induction of tumors in nude mice. Using the yeast two-hybrid assay, we identified genes associated with retinoid-IFN-induced mortality-19 (GRIM19), which interacts directly with vIRF1, both in vivo and in vitro. The N-terminal region of vIRF1 is required for binding GRIM19. Colocalization of vIRF1 and GRIM19 was observed in 293T cells. The vIRF1 protein deregulates GRIM19-induced apoptosis in the presence of IFN/all-trans-retinoic acid (RA) and inhibits IFN/RA-induced cell death. Another DNA tumor viral protein, human papillomavirus type 16 E6, also binds GRIM19, suggesting that this is a general target of viral proteins. Our results collectively indicate that vIRF1 modulates IFN/RA-cell death signals via interactions with GRIM19.

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15

Yu, Sun, Zhang Xi, Chen Hai-Yan, Chi Ya-Li, Xiong Shao-Hu, Zhang Chuan-Sen, Yang Xiang-Qun, Guo Jin-Ping, Lin Hai-Yan, and Dong Lei. "Interferon regulatory factor-1 as a positive regulator for high glucose-induced proliferation of vascular smooth muscle cells." Journal of Cellular Biochemistry 113, no. 8 (June 15, 2012): 2671–78. http://dx.doi.org/10.1002/jcb.24142.

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16

Tallam, Aravind, Thaneer M. Perumal, Paul M. Antony, Christian Jäger, Joëlle V. Fritz, Laurent Vallar, Rudi Balling, Antonio del Sol, and Alessandro Michelucci. "Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages." PLOS ONE 11, no. 2 (February 12, 2016): e0149050. http://dx.doi.org/10.1371/journal.pone.0149050.

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17

Kapellen, Thomas, Angela Galler, Wieland Kiess, and Klemens Raile. "Ätiopathogenese des Typ-1-Diabetes mellitus." Kinder- und Jugendmedizin 5, no. 04 (2005): 184–91. http://dx.doi.org/10.1055/s-0037-1617864.

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ZusammenfassungDer Diabetes mellitus Typ 1 ist eine durch Umweltfaktoren ausgelöste Autoimmunerkrankung, die genetisch empfängliche Personen trifft. Begünstigende Umweltfaktoren sind Nahrungsmittel, wie Kuhmilchprotein, virale Infekte und unterschiedliche Umweltgifte, wie Nitrosamine. Typ-1-Diabetes wird als zellvermittelte Autoimmunerkrankung mit progressiver Zerstörung der insulinproduzierenden Beta-Zellen verstanden. Dabei spielt die Aktivierung proapoptotischer Signalwege (programmierter Zelltod) durch inflammatorische Zytokine eine Schlüsselrolle beim Zelltod der β-Zellen. Den T-Lymphozyten vom so genannten Helfer-Typ (Th1) wird dabei eine zentrale Rolle zugeschrieben. Zytokine, die überwiegend von Th1-Zellen sezerniert werden, sind Interleukin-1 (IL-1)β, Interferon (IFN)-γ und Tumor-Nekrose-Faktor (TNF)α. Die Produktion dieser proinflammatorischen Zytokine wird einer Störung im fein abgestimmten Gleichgewicht zwischen Th1- und Th2-Helfer-T-Zellen zugeschrieben und führt zu einer selektiven Aktivierung von Beta-Zell-spezifischen, zytotoxischen Effektor-T-Zellen. Durch eine weitere Aufschlüsselung der Ätiopathogenese des Typ-1-Diabetes mellitus sollen neue Strategien in dessen Prävention und Heilung entwickelt werden.

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18

Huang, Kai, Monica L. Bailey, and Dwayne L. Barber. "Stress Erythropoiesis Elicits a Program of Gene Regulation That Overlaps with Interferon-γ." Blood 104, no. 11 (November 16, 2004): 2161. http://dx.doi.org/10.1182/blood.v104.11.2161.2161.

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Abstract Erythropoietin (EPO), the primary cytokine regulator of red blood cell production, acts through binding to its cognate receptor (EPO-R), which is primarily expressed on erythroid precursors. Knockout studies have illustrated a critical role for EPO, EPO-R and the downstream tyrosine kinase JAK2 in embryogenesis as mice lacking any of these components die from a fatal anemia at E13.5. These data suggest that EPO-R and/or JAK2 are required to promote erythropoiesis in vivo. EPO provides mitogenic, differentiative and cell survival signals to erythroid progenitors. We have performed microarray studies to identify target genes regulated by EPO in cell lines and primary cells. We utilized an erythroid cell line (HCD-57), a myeloid cell line stably expressing the EPO-R (Ba/F3-EPO-R), fetal liver cells isolated from E13.5 mice as well as splenocytes isolated from Phenylhydrazine (PHZ)-primed adult mice. Fetal liver cells permit the study of normal erythropoiesis in a fetal setting whereas the PHZ-primed erythroblasts permit analysis of stress erythropoiesis in adult mice. We harvested cells at 1, 8, 12 and 24 hr after EPO stimulation which correspond to immediate early gene induction (1 hr), S phase entry (8 hr) and G2/M (24 hr) time points. RNA was prepared and hybridized to the Affymetrix U74A mouse chip. Data was analyzed and only those genes with statistical significance (p < 0.05) were considered for further characterization. Analysis of the 1 hr time points has revealed that six genes are co-regulated by EPO in all four cellular environments. Included within this co-hort are the Suppressor of Cytokine Signaling genes (Cis, SOCS-1 and SOCS-3) and Myc, as well as two novel genes. We compared our datasets with other published analyses. The Williams laboratory has identified an Interferon-Stimulated Gene “ISG” data set corresponding to genes induced by Type I or Type II Interferon’s. We queried our PHZ-primed erythroblast data set against the Williams ISG database. Of the 305 human genes in the ISG database, 218 are expressed on the Affymetrix chip. We searched our dataset for genes that are induced 1.5-fold or greater at 2 of 4, 3 of 4 or 4 of 4 time points. Thirty-four genes are also stimulated by EPO in PHZ-primed erythroblasts including classical IFN-regulated genes such as Interferon-regulator factor-1 (IRF-1), Interferon-stimulated gene-15 (ISG-15), Interferon-induced transmembrane protein 3-like (IFITM-3l), Protein Kinase R (PKR) and Signal Transducer and Activator of Transcription-1 (STAT1). We have previously demonstrated that STAT1 is a negative regulator of murine erythropoiesis utilizing STAT1-deficient mice. We also analyzed immediate early gene regulation in fetal liver cells and PHZ-primed erythroblasts isolated from STAT1-deficient mice stimulated with EPO for 1 hr. These data were compared with the relevant wild type data sets. EPO stimulates the induction of the ubiquitin-like protein, ISG-15 in both wild type and STAT1−/− erythroblasts. Several signaling proteins have been shown to be covalently modified by ISG-15 including STAT1. ISG-15 is removed from ISGylated products by the deubiquitinating enzyme, Ubp43. EPO stimulates a rapid accumulation of Ubp43 in wild type cells, however, EPO fails to induce Ubp43 mRNA in STAT1-deficient fetal liver and PHZ-primed erythroblasts. Experiments are underway to confirm that the mechanism by which STAT1 exerts negative regulation of erythropoiesis is via upregulation of the deubiquitinating enzyme, Ubp43.

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19

Uematsu, Satoshi, Shintaro Sato, Masahiro Yamamoto, Tomonori Hirotani, Hiroki Kato, Fumihiko Takeshita, Michiyuki Matsuda, et al. "Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction." Journal of Experimental Medicine 201, no. 6 (March 14, 2005): 915–23. http://dx.doi.org/10.1084/jem.20042372.

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Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-α in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-α production was abolished in Irak-1–deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-κB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1–deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-α induction in pDCs.

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20

Cai, Junchao, Junglim Lee, Ewa Jankowska-Gan, Richard Derks, Jos Pool, Tuna Mutis, Els Goulmy, and William J. Burlingham. "Minor H Antigen HA-1–specific Regulator and Effector CD8+ T Cells, and HA-1 Microchimerism, in Allograft Tolerance." Journal of Experimental Medicine 199, no. 7 (April 5, 2004): 1017–23. http://dx.doi.org/10.1084/jem.20031012.

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The role of the hematopoietic lineage-restricted minor histocompatibility (H) antigen HA-1 in renal allograft tolerance was explored. We obtained peripheral blood samples from three recipients of histocompatibility leukocyte antigen (HLA)–matched, HA-1–mismatched renal transplants, one of which had discontinued immunosuppression >30 yr ago while sustaining normal kidney function. Peripheral blood mononuclear cells (PBMCs) were injected into the footpads of severe combined immunodeficiency mice to measure human delayed type hypersensitivity (DTH) responses. All three patients manifested regulated DTH responses to HA-1H peptide. By differential tetramer staining intensities, we observed two distinct minor H antigen HA-1–specific CD8+ T cell subsets. The one that stained dimly had the characteristics of a T regulatory (TR) cell and produced interleukin (IL) 10 and/or transforming growth factor (TGF) β. These HA-1–specific TR cells coexisted with bright tetramer-binding CD8+ T effector (TE) cells. The CD8+ TE cells mediated HA-1–specific DTH and produced interferon-γ. Suppression of these TE functions by TR cells was TGFβ, IL-10, and cytotoxic T lymphocyte–associated antigen 4 dependent. In addition, HA-1 microchimerism was detected in two recipients, primarily in the dendritic cell fraction of the PBMCs. This is the first demonstration of coexisting CD8+ memory TR and TE cells, both specific for the same HA-1 antigen, in the context of renal allograft tolerance.

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Doody, Gina, Sophie Stephenson, and Reuben Tooze. "BLIMP-1 Is a Target of Cellular Stress and Downstream of the Unfolded Protein Response." Blood 106, no. 11 (November 16, 2005): 2207. http://dx.doi.org/10.1182/blood.v106.11.2207.2207.

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Abstract Human B lymphocyte-induced maturation protein-1 (BLIMP-1) was originally described as a repressor of the interferon-beta response to viral infection. Subsequently, the murine orthologue was identified as a regulator of plasma cell differentiation. The involvement of BLIMP-1 in hemopoietic differentiation is not restricted to the B-cell lineage as BLIMP-1 is induced during differentiation of myeloid progenitors. During in vitro macrophage and plasma cell differentiation the expression of BLIMP-1 is cytokine driven. However, the BLIMP-1 response to virus infection can be reproduced by transfection with double-stranded RNA (dsRNA), indicating that BLIMP-1 is a target of dsRNA responsive signaling pathways. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated kinase, PKR. PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2α) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum (ER) PKR-homologue is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested the hypothesis that BLIMP-1 may represent a shared target of signaling pathways in the response to cellular stresses such as virus infection and the UPR. In this study we demonstrate that BLIMP-1 is rapidly upregulated during the UPR in human myeloid and B-cell lines. This response is conserved in primary murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription, with enhanced recruitment of RNA polymerase II to the BLIMP-1 promoter. Furthermore the stress response is limited to induction of BLIMP-1α mRNA and does not affect levels of an alternate transcript encoding a truncated protein, BLIMP-1β. The common induction of BLIMP-1 mRNA by stimuli which trigger the UPR supports the hypothesis that BLIMP-1 is a target of the eIF2α kinase family. To test this hypothesis directly, we employed a dominant negative mutant PERK. Our data demonstrate that the BLIMP-1 response to UPR stress is dependent on an intact PERK signaling pathway. Collectively our results provide evidence for a novel link between cellular stress, the eIF2α kinase family and a regulator of differentiation in macrophages and B-cells.

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Fantuzzi, Giamila, Adrian J. Puren, Matthew W. Harding, David J. Livingston, and Charles A. Dinarello. "Interleukin-18 Regulation of Interferon γ Production and Cell Proliferation as Shown in Interleukin-1β–Converting Enzyme (Caspase-1)-Deficient Mice." Blood 91, no. 6 (March 15, 1998): 2118–25. http://dx.doi.org/10.1182/blood.v91.6.2118.

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Abstract Interleukin-18 (IL-18) is a costimulatory factor for interferonγ (IFNγ) production. Processing of pro–IL-18 by IL-1β–converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with wild-type (WT) mice, splenocytes from ICE-deficient mice produced low IFNγ after lipopolysaccharide (LPS) or zymosan (50% and 80% reduction). In contrast, IFNγ production was unimpaired in ICE-deficient mice using Concanavalin A (Con A). Comparable results were obtained when endogenous IL-18 was blocked with a neutralizing antibody. LPS-induced IFNγ was also reduced by an ICE inhibitor. Exogenous IL-18 augmented zymosan-induced IFNγ production in WT mice. In ICE-deficient cells, IFNγ production was only partially restored by IL-18. The reduced levels of IFNγ in ICE-deficient mice were not due to a lack of IL-12, because zymosan induced IL-12 equally in WT and in ICE-deficient mice. IFNγ is an important regulator of cell proliferation. In accordance, splenocytes from ICE-deficient mice proliferated more when stimulated with LPS, but not with Con A. Furthermore, in ovalbumin-sensitized ICE-deficient mice, proliferation of lymph node cells in response to the specific antigen was not altered. Exogenous IFNγ inhibited, whereas blockade of endogenous IFNγ or IL-18 increased, LPS induced splenocyte proliferation both in WT and in ICE-deficient mice. Our results show that IL-18 is an IL-12–independent regulator of IFNγ production and of cell proliferation induced by microbial stimuli. However, ICE-dependent processing of IL-18 is not needed for response to mitogens or antigens.

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23

Fantuzzi, Giamila, Adrian J. Puren, Matthew W. Harding, David J. Livingston, and Charles A. Dinarello. "Interleukin-18 Regulation of Interferon γ Production and Cell Proliferation as Shown in Interleukin-1β–Converting Enzyme (Caspase-1)-Deficient Mice." Blood 91, no. 6 (March 15, 1998): 2118–25. http://dx.doi.org/10.1182/blood.v91.6.2118.2118_2118_2125.

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Interleukin-18 (IL-18) is a costimulatory factor for interferonγ (IFNγ) production. Processing of pro–IL-18 by IL-1β–converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with wild-type (WT) mice, splenocytes from ICE-deficient mice produced low IFNγ after lipopolysaccharide (LPS) or zymosan (50% and 80% reduction). In contrast, IFNγ production was unimpaired in ICE-deficient mice using Concanavalin A (Con A). Comparable results were obtained when endogenous IL-18 was blocked with a neutralizing antibody. LPS-induced IFNγ was also reduced by an ICE inhibitor. Exogenous IL-18 augmented zymosan-induced IFNγ production in WT mice. In ICE-deficient cells, IFNγ production was only partially restored by IL-18. The reduced levels of IFNγ in ICE-deficient mice were not due to a lack of IL-12, because zymosan induced IL-12 equally in WT and in ICE-deficient mice. IFNγ is an important regulator of cell proliferation. In accordance, splenocytes from ICE-deficient mice proliferated more when stimulated with LPS, but not with Con A. Furthermore, in ovalbumin-sensitized ICE-deficient mice, proliferation of lymph node cells in response to the specific antigen was not altered. Exogenous IFNγ inhibited, whereas blockade of endogenous IFNγ or IL-18 increased, LPS induced splenocyte proliferation both in WT and in ICE-deficient mice. Our results show that IL-18 is an IL-12–independent regulator of IFNγ production and of cell proliferation induced by microbial stimuli. However, ICE-dependent processing of IL-18 is not needed for response to mitogens or antigens.

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24

Song, Soonhwa, Jae-Jin Lee, Hee-Jung Kim, Jeong Yoon Lee, Jun Chang, and Kong-Joo Lee. "Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus." Molecular and Cellular Biology 36, no. 7 (January 25, 2016): 1136–51. http://dx.doi.org/10.1128/mcb.00744-15.

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This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.

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Sassano, Antonella, Evangelos Mavrommatis, Ahmet Dirim Arslan, Barbara Kroczynska, Elspeth M. Beauchamp, Satya Khuon, Ten-Leong Chew, et al. "Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells." Molecular and Cellular Biology 35, no. 15 (May 26, 2015): 2684–98. http://dx.doi.org/10.1128/mcb.00019-15.

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We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1),MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression.

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Marteau, Frédéric, Nathalie Suarez Gonzalez, David Communi, Michel Goldman, Jean-Marie Boeynaems, and Didier Communi. "Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells." Blood 106, no. 12 (December 1, 2005): 3860–66. http://dx.doi.org/10.1182/blood-2005-05-1843.

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Extracellular adenosine triphosphate affects the maturation of human monocyte–derived dendritic cells (DCs), mainly by inhibiting T-helper 1 (Th1) cytokines, promoting Th2 cytokines, and modulating the expression of costimulatory molecules. In this study, we report that adenosine triphosphate (ATP) can induce immunosuppression through its action on DCs, defining a new role for extracellular nucleotides. Microarray analysis of ATP-stimulated human DCs revealed inter alia a drastic up-regulation of 2 genes encoding mediators involved in immunosuppression: thrombospondin-1 (TSP-1) and indoleamine 2,3-dioxygenase (IDO). The release of TSP-1 by DCs in response to ATP was confirmed at the protein level by enzyme-linked immunosorbent assay (ELISA), immunodetection, and mass spectrometry analysis, and has an antiproliferative effect on T CD4+ lymphocytes through TSP-1/CD47 interaction. Our pharmacologic data support the involvement of purinergic receptor P2Y11 in this ATP-mediated TSP-1 secretion. We demonstrate also that ATP significantly potentiates the up-regulation of IDO—a negative regulator of T lymphocyte proliferation—and kynurenine production initiated by interferon-γ (IFN-γ) in human DCs.Thus, extracellular ATP released from damaged cells and previously considered as a danger signal is also a potent regulator of mediators playing key roles in immune tolerance. Consequently, nucleotides' derivatives may be considered as useful tools for DC-based immunotherapies.

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An, Ni, Jianyuan Zhao, and Shan Cen. "Interferon-Stimulated SAMHD1 Restricts Hepatitis C Virus Replication." Proceedings 50, no. 1 (June 13, 2020): 42. http://dx.doi.org/10.3390/proceedings2020050042.

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Human SAMHD1 is an IFN-induced dNTP triphosphatase that is able to restrict HIV-1 replication, whereas its role in innate immunity against virus infection remains largely unexplored. In this work, we provided evidence that SAMHD1 functions as an anti-HCV host factor. We found that overexpression of SAMHD1 resulted in significant inhibition on the replication of HCV, but not other RNA viruses including influenza A virus and EV71. SAMHD1 knockdown partially relieved the inhibitory effect of IFN on HCV, suggesting its important role in the innate immune response against HCV. Mechanistic studies revealed that SAMHD1 targets viral RNA replication without impact on both protein translation and virus entry. Transcriptome analysis showed a broad inhibitory effect of SAMHD1 on host genes involved in cholesterol and fatty acid biosynthesis. In particular, SAMHD1 was shown to downregulate the mRNA abundance of SREBP1, a master transcriptional regulator of de novo lipid biosynthesis, impairing the formation of lipid droplets. Restoring intracellular lipid levels by either exogenous lipid addition or SREBP1 overexpression counteracted the restriction of HCV by SAMHD1, providing evidence that SAMHD1 inhibits the replication of HCV by suppressing host cholesterol and fatty acid biosynthesis. Together, these data unveil, for the first time, a novel antiviral mechanism of SAMHD1 and open new avenues for the development of novel anti-HCV therapeutics.

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Lao, Mengyi, Xiaozhen Zhang, Tao Ma, Jian Xu, Hanshen Yang, Yi Duan, Honggang Ying, et al. "Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells." Oncogene 40, no. 17 (April 6, 2021): 3136–51. http://dx.doi.org/10.1038/s41388-021-01763-z.

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AbstractTherapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

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Iezaki, Takashi, Kazuya Fukasawa, Gyujin Park, Tetsuhiro Horie, Takashi Kanayama, Kakeru Ozaki, Yuki Onishi, et al. "Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway." Molecular and Cellular Biology 36, no. 19 (July 5, 2016): 2451–63. http://dx.doi.org/10.1128/mcb.01075-15.

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Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murineIfrd1increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion ofIfrd1in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impairedin vitroinIfrd1-deleted bone marrow macrophages (BMMs).Ifrd1deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodelingin vivoand represents a therapeutic target for bone diseases.

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You, Min, De-Hua Yu, and Gen-Sheng Feng. "Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 2416–24. http://dx.doi.org/10.1128/mcb.19.3.2416.

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ABSTRACT Shp-2 is an SH2 domain-containing protein tyrosine phosphatase. Although the mechanism remains to be defined, substantial experimental data suggest that Shp-2 is primarily a positive regulator in cell growth and development. We present evidence here that Shp-2, while acting to promote mitogenic signals, also functions as a negative effector in interferon (IFN)-induced growth-inhibitory and apoptotic pathways. Treatment of mouse fibroblast cells lacking a functional Shp-2 with IFN-α or IFN-γ resulted in an augmented suppression of cell viability compared to that of wild-type cells. To dissect the molecular mechanism, we examined IFN-induced activation of signal transducers and activators of transcription (STATs) by electrophoretic mobility shift assay, using a specific DNA probe (hSIE). The amounts of STAT proteins bound to hSIE upon IFN-α or IFN-γ stimulation were significantly increased in Shp-2−/− cells. Consistently, tyrosine phosphorylation levels of Stat1 upon IFN-γ treatment and, to a lesser extent, upon IFN-α stimulation were markedly elevated in mutant cells. Furthermore, IFN-γ induced a higher level of caspase 1 expression in Shp-2−/− cells than in wild-type cells. Reintroduction of wild-type Shp-2 protein reversed the hypersensitivity of Shp-2−/− fibroblasts to the cytotoxic effect of IFN-α and IFN-γ. Excessive activation of STATs by IFNs was also diminished in mutant cells in which Shp-2 had been reintroduced. Together, these results establish that Shp-2 functions as a negative regulator of the Jak/STAT pathway. We propose that Shp-2 acts to promote cell growth and survival through two mechanisms, i.e., the stimulation of growth factor-initiated mitogenic pathways and the suppression of cytotoxic effect elicited by cytokines, such as IFNs.

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Wang, Feng, Weiwei Xia, Feng Liu, Ji Li, Guang Wang, and Jun Gu. "Interferon regulator factor 1/retinoic inducible gene I (IRF1/RIG-I) axis mediates 25-hydroxycholesterol-induced interleukin-8 production in atherosclerosis." Cardiovascular Research 93, no. 1 (October 6, 2011): 190–99. http://dx.doi.org/10.1093/cvr/cvr260.

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Zhang, Luwen, and Joseph S. Pagano. "Interferon Regulatory Factor 7 Is Induced by Epstein-Barr Virus Latent Membrane Protein 1." Journal of Virology 74, no. 3 (February 1, 2000): 1061–68. http://dx.doi.org/10.1128/jvi.74.3.1061-1068.2000.

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ABSTRACT Infection by Epstein-Barr virus (EBV) generates several types of latency with different profiles of gene expression but with expression of Epstein-Barr nuclear antigen 1 (EBNA-1) in common. TheBamHI Q promoter (Qp) is used for the transcription of EBNA-1 mRNA in type I latency, which is an EBV infection state exemplified by Burkitt's lymphoma (BL). However, Qp is inactive in type III latency, and other promoters (C/Wp) are used for transcription of EBNA-1, which raises the question of how usage of these promoters is governed. Interferon (IFN) regulatory factor 7 (IRF-7) was identified first as a negative regulator of Qp. Expression of IRF-7 is associated with EBV type III latency, where Qp is inactive, but not with type I latency, raising the possibility that a viral gene product(s) expressed in type III latency might induce IRF-7 and repress Qp. Here, detailed analysis of the expression of IRF-7 revealed that it is associated with the expression of EBV latent membrane protein 1 (LMP-1) and that LMP-1 stimulates the expression of IRF-7 in type III latency in which Qp is inactive. In contrast, LMP-1 is not expressed in type I latency cells in which Qp is active. LMP-1 represses the constitutive activity of Qp reporter constructs. Mutational analysis of Qp reporter constructs revealed that the Qp IFN-stimulated response element (ISRE) is essential for the repression by LMP-1. Furthermore, LMP-1 reduced EBNA-1 mRNA derived from Qp only in type I cells in which IRF-7 could be induced. Finally, IFN-α, but not IFN-γ, repressed endogenous Qp activity, which is consistent with the ability of IFN-α to induce IRF-7. Thus, IRF-7 may mediate repression of Qp by LMP-1. The induction of IRF-7 by LMP-1 may be relevant to the silencing of Qp in EBV type III latency.

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Magg, Thomas, Tsubasa Okano, Lars M. Koenig, Daniel F. R. Boehmer, Samantha L. Schwartz, Kento Inoue, Jennifer Heimall, et al. "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency." Science Immunology 6, no. 60 (June 18, 2021): eabf9564. http://dx.doi.org/10.1126/sciimmunol.abf9564.

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Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

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Berlintina, Duta, Agus Karyanto, Rugayah, and Kuswanta Futas Hidayat. "Effects of Organic Matters as Source of the Plant Growth Regulator on Seedling Growth of Mangosteen (Garcinia mangostana L.)." Jurnal Hortikultura Indonesia 11, no. 2 (December 26, 2020): 110–19. http://dx.doi.org/10.29244/jhi.11.2.110-119.

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Manggis (Garcinia mangostana L.) merupakan salah satu buah yang memiliki potensi cukup tinggi di pasaran dibandingkan dengan buah tropis lainnya, namun produksi manggis masih sangat rendah. Kendala utama dalam budidaya tanaman manggis yaitu lambatnya pertumbuhan tanaman manggis akibat minimnya akar–akar lateral, khususnya tanaman manggis asal biji, oleh karena itu perlu dilakukan upaya untuk mempercepat pertumbuhan seedling manggis. Penelitian ini bertujuan untuk mengoptimalkan pertumbuhan seedling manggis dengan penggunaan zat pengatur tumbuh alami ekstrak bawang merah dan ekstrak kecambah dengan frekuensi pemberian yang berbeda. Penelitian ini dilaksanakan di Rumah Kaca Fakultas Pertanian, Universitas Lampung dari bulan Oktober 2018 hingga Maret 2019. Perlakuan disusun secara faktorial (2x3) dalam rancangan acak kelompok (RAK) yang diulang sebanyak tiga kali. Faktor pertama adalah jenis ekstrak bawang merah dan kecambah, sedangkan faktor kedua adalah frekuensi pemberian 1, 2, dan 3 kali. Data yang diperoleh dianalisis dengan analisis ragam dan dilakukan pemisahan nilai tengah dengan uji orthogonal kontras pada taraf nyata 5%. Hasil penelitian menunjukkan bahwa pemberian bahan organik sumber ZPT frekuensi satu kali lebih baik dalam meningkatkan bobot basah seedling manggis dibandingkan frekuensi dua atau tiga kali dengan selisih bobot 0.47 g (12.71%). Perkembangan akar seedling manggis akan meningkat apabila diberi perlakuan ekstrak kecambah dengan frekuensi satu kali, tetapi apabila yang digunakan ekstrak bawang merah maka frekuensi pemberian dua atau tiga kali.

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Weaver, Brian K., K. Prasanna Kumar, and Nancy C. Reich. "Interferon Regulatory Factor 3 and CREB-Binding Protein/p300 Are Subunits of Double-Stranded RNA-Activated Transcription Factor DRAF1." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1359–68. http://dx.doi.org/10.1128/mcb.18.3.1359.

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ABSTRACT Cells respond to viral infection or double-stranded RNA with the transcriptional induction of a subset of alpha/beta interferon-stimulated genes by a pathway distinct from the interferon signal pathway. The transcriptional induction is mediated through a DNA sequence containing the alpha/beta interferon-stimulated response element (ISRE). We previously identified a novel transcription factor, designated double-stranded RNA-activated factor 1 (DRAF1), that recognizes this response element. The DNA-binding specificity of DRAF1 correlates with transcriptional induction, thereby distinguishing it as a positive regulator of alpha/beta interferon-stimulated genes. Two of the components of DRAF1 have now been identified as interferon regulatory factor 3 (IRF-3) and the transcriptional coactivator CREB-binding protein (CBP)/p300. We demonstrate that IRF-3 preexists in the cytoplasm of uninfected cells and translocates to the nucleus following viral infection. Translocation of IRF-3 is accompanied by an increase in serine and threonine phosphorylation. Coimmunoprecipitation analyses of endogenous proteins demonstrate an association of IRF-3 with the transcriptional coactivators CBP and p300 only subsequent to infection. In addition, antibodies to the IRF-3, CBP, and p300 molecules react with DRAF1 bound to the ISRE target site of induced genes. The cellular response that leads to DRAF1 activation and specific gene expression may serve to increase host survival during viral infection.

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Yang, Kai, Hexin Shi, Rong Qi, Shaogang Sun, Yujie Tang, Bianhong Zhang, and Chen Wang. "Hsp90 Regulates Activation of Interferon Regulatory Factor 3 and TBK-1 Stabilization in Sendai Virus-infected Cells." Molecular Biology of the Cell 17, no. 3 (March 2006): 1461–71. http://dx.doi.org/10.1091/mbc.e05-09-0853.

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Interferon regulatory factor 3 (IRF3) plays a crucial role in mediating cellular responses to virus intrusion. The protein kinase TBK1 is a key regulator inducing phosphorylation of IRF3. The regulatory mechanisms during IRF3 activation remain poorly characterized. In the present study, we have identified by yeast two-hybrid approach a specific interaction between IRF3 and chaperone heat-shock protein of 90 kDa (Hsp90). The C-terminal truncation mutant of Hsp90 is a strong dominant-negative inhibitor of IRF3 activation. Knockdown of endogenous Hsp90 by RNA interference attenuates IRF3 activation and its target gene expressions. Alternatively, Hsp90-specific inhibitor geldanamycin (GA) dramatically reduces expression of IRF3-regulated interferon-stimulated genes and abolishes the cytoplasm-to-nucleus translocation and DNA binding activity of IRF3 in Sendai virus-infected cells. Significantly, virus-induced IRF3 phosphorylation is blocked by GA, whereas GA does not affect the protein level of IRF3. In addition, TBK1 is found to be a client protein of Hsp90 in vivo. Treatment of 293 cells with GA interferes with the interaction of TBK1 and Hsp90, resulting in TBK1 destabilization and its subsequent proteasome-mediated degradation. Besides maintaining stability of TBK1, Hsp90 also forms a novel complex with TBK1 and IRF3, which brings TBK1 and IRF3 dynamically into proximity and facilitates signal transduction from TBK1 to IRF3. Our study uncovers an essential role of Hsp90 in the virus-induced activation of IRF3.

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Hardy, Matthew P., Catherine M. Owczarek, Suzana Trajanovska, Xiang Liu, Ismail Kola, and Paul J. Hertzog. "The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties." Blood 97, no. 2 (January 15, 2001): 473–82. http://dx.doi.org/10.1182/blood.v97.2.473.

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Abstract The ability to modify responses to type I interferons (IFNs) could alter processes such as hematopoiesis and immunity, which involve endogenous IFNs and responses to exogenous IFNs. The data presented here support a significant role for a recently identified soluble isoform of the murine type I IFN receptor, muIfnar-2a, as an efficient regulator of IFN responses. The messenger RNA (mRNA) transcript encoding muIfnar-2a is generally more abundant than that encoding the transmembrane isoform, muIfnar-2c. Furthermore, the ratio ofmuIfnar-2a:2c transcripts varied from more than 10:1 in the liver and other organs to less than 1:1 in bone-marrow macrophages, indicating independent regulation of the 2 transcripts encoding receptor isoforms and suggesting that the soluble muIfnar-2a levels are biologically relevant in some organs. Western blot analysis showed that soluble muIfnar-2 was present at high levels in murine serum and other biologic fluids and bound type I IFN. Recombinant muIfnar-2a competitively inhibited the activity of both IFNα and β in reporter assays using the L929 cell line and in antiproliferative and antiviral assays using primary cells. Surprisingly, using primary thymocytes fromIfnar-2−/− mice, recombinant muIfnar-2a formed a complex with IFN α or β and muIfnar-1 at the cell surface and transmitted an antiproliferative signal. These data indicate potential dual actions of soluble muIfnar-2 and imply that a signal can be transduced through the Ifnar-1 chain of the receptor complex in the absence of the cytoplasmic domain of Ifnar-2. Therefore, our results suggest that soluble Ifnar-2 is an important regulator of endogenous and systemically administered type I IFN.

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Cui, Hao, Ying Liu, and Yifei Huang. "Roles of TRIM32 in Corneal Epithelial Cells After Infection with Herpes Simplex Virus." Cellular Physiology and Biochemistry 43, no. 2 (2017): 801–11. http://dx.doi.org/10.1159/000481563.

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Background: Epithelial cells play important roles as a critical barrier in protecting the cornea from microbial pathogens infection. Methods: In this study, we were aiming to investigate the role of E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) in corneal epithelial cells in response to Herpes Simplex Virus type 1 (HSV-1) infection and to elucidate the underlying mechanisms. Results: We found the expression of TRIM32 was increased after infected with HSV-1 both in murine corneas and cultured human epithelial (HCE) cells. Furthermore, knockdown of the expression of TRIM32 significantly aggravated HSV-1 induced herpetic stromal keratitis (HSK) in mice and promoted the replication of HSV-1 in cultured HCE cells. We also observed that silencing of TRIM32 resulted in the decreased expression of IFN-β and suppressed activation of interferon regulatory factor 3 (IRF3) both in vivo and in vitro. Finally, we found TRIM32 positively regulate IFN-β production in corneal epithelial cells through promoting K63-linked polyubiquitination of stimulator of interferon genes (STING). Conclusion: In conclusion, our data suggested that TRIM32 as a crucial positive regulator of HSV-1 induced IFN-β production in corneal epithelial cells, and it played a predominant role in clearing HSV-1 from the cornea.

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Buggele, William A., Katherine E. Krause, and Curt M. Horvath. "Small RNA Profiling of Influenza A Virus-Infected Cells Identifies miR-449b as a Regulator of Histone Deacetylase 1 and Interferon Beta." PLoS ONE 8, no. 9 (September 26, 2013): e76560. http://dx.doi.org/10.1371/journal.pone.0076560.

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Sun, Lin, Anthony J. St. Leger, Cheng-Rong Yu, Chang He, Rashid M. Mahdi, Chi-Chao Chan, Hongsheng Wang, Herbert C. Morse, and Charles E. Egwuagu. "Interferon Regulator Factor 8 (IRF8) Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells." PLOS ONE 11, no. 5 (May 12, 2016): e0155420. http://dx.doi.org/10.1371/journal.pone.0155420.

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Wang, Yun, Kelvin Zhang, Peter Georgiev, Steven Wells, Haiyan Xu, Brian M. Lacey, Zangwei Xu, et al. "Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function." PLOS ONE 15, no. 12 (December 3, 2020): e0243145. http://dx.doi.org/10.1371/journal.pone.0243145.

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Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.

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Journal, Journal. "RESPON PERTUMBUHAN DAN HASIL BAWANG MERAH (Allium ascalonicum) TERHADAP PEMBERIAN ZAT PENGATUR TUMBUH DAN PUPUK NPK PADA TANAH SPODOSOL (The Growth and Yield Response of Onion (Allium ascalonicum)of Giving The Plant Growth Regulators (PGR) and NPK Fertili." AgriPeat 18, no. 02 (August 29, 2019): 105–12. http://dx.doi.org/10.36873/agp.v18i02.13.

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ABSTRACT The purpose of this study was to determine the growth and yield of onion that were given growth regulator (PGR) and NPK fertilizer on spodosol. This study used Randomized Block Design (RBD) of factorial pattern with two factors: (1) growth regulator (0, 3, 6, and 9 mL.L-1 ), and (2) NPK fertilizer (0, 150, 300, and 450 kg ha-1). The results of this study showed tha giving of PGR increased the crop growth rate of plants aged 14-21 day after planting (1.057 g.m-2 day -1) and 21-28 day after planting (1.089 g.m-2 day-1) with the best concentration of 6 mL.L-1 water. The best NPK fertilizer dosage of 300 kg.ha-1 was able to increase plant height at 42 day after planting (46,89 cm), leaf area 21, 28 and 35 day after planting (541,22 cm2, 717,37 cm2, and 714 , 29 cm2), weight of fresh stover (75,50 g), weight of dry stover (66,19 g) and tuber weight per plot (4,520,25 g). Key words : onion, plant growth regulator (PGR), NPK, spodosol ABSTRAK Tujuan penelitian untuk mengetahui pertumbuhan dan hasil tanaman bawang merah yang diberi zat pengatur tumbuh (ZPT) dan pupuk NPK pada tanah spodosol. Penelitian ini menggunakan menggunakan Rancangan Acak Kelompok (RAK) pola faktorial dengan dua faktor, yaitu : (1) zat pengatur tumbuh (0, 3, 6, dan 9 mL.L-1 air), dan (2) pupuk NPK ( 0, 150, 300, dan 450 kg.ha-1). Hasil penelitian menunjukkan bahwa pemberian ZPT meningkatkan laju pertumbuhan tanaman umur 14-21 hst (1,057 g.m-2. hari -1) dan 21-28 hst (1,089 g.m-2. hari -1) dengan konsentrasi terbaik 6 mL.L-1 air. Dosis pupuk NPK terbaik 300 kg.ha-1 mampu meningkatkan luas daun umur 21, 28 dan 35 hst, masing-masing 541,22 cm2, 717,37 cm2, dan 714,29 cm2, bobot brangkasan segar (75,50 g), bobot brangkasan kering (66,19 g) dan bobot umbi per petak (4.520,25 g). kata kunci: bawang merah, zat pengatur tumbuh (ZPT), NPK, spodosol

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Kleppe, Maria, Matthew H. Spitzer, Sheng Li, Lauren Dong, Efthymia Papalexi, Corinne Hill, Sofie De Groote, et al. "JAK1 As a Convergent Regulator of Hematopoietic Stem Cell Function and Stress Hematopoiesis." Blood 128, no. 22 (December 2, 2016): 722. http://dx.doi.org/10.1182/blood.v128.22.722.722.

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Abstract Cytokine-mediated signal transduction is critical to hematopoiesis, immune responses, and other physiological processes. Aberrant production and secretion of pro-inflammatory cytokines disturbs homeostasis and proper immune function and if persistent results in symptoms of chronic inflammation. Previous studies have illustrated the importance of JAK1 as an effector of cytokine signaling, including in immunological and neoplastic diseases such that selective JAK1 inhibition is currently being investigated in clinical trials. However, the role of Jak1 in hematopoietic stem cell (HSC) function has not been delineated. This has led us to investigate the impact of loss of Jak1 signaling on HSC function by developing a novel conditional Jak1 knockout allele (Fig. 1a). Mice with conditional deletion of Jak1 in the hematopoietic system (hereafter referred to as Jak1 KO) are characterized by leukocytosis (Jak1 KO avg. 6.34K/ul, Jak1 WT avg. 10.76K/ul, P<0.01), and reduced spleen (Jak1 KO avg. 73.76mg, Jak1 WT avg. 98.86mg, P<0.01) and thymus weights (Jak1 KO avg. 49.31mg, Jak1 WT avg. 80.82mg, P<0.01). High dimensional single cell analysis of the hematopoietic compartment of these mice using mass cytometry showed that conditional Jak1 loss in hematopoietic cells attenuates B cell and NK cell differentiation in vivo, and results in differentiation towards the myeloid lineage at the expense of lymphoid fate commitment. Further, we observed a significant reduction of lineage-Sca1+cKit+ (LSK) cells in the bone marrow of Jak1 KO mice, including a decrease in CD34-Flk2- long-term HSCs (LT-HSCs) and in CD34+Flk2- short-term HSCs (ST-HSCs) (Fig.1b). Jak1-deficient cells formed fewer colonies in colony formation unit assays, which was also seen when clonogenic assays were performed in the presence of JAK1 inhibitor GLPG0634. Most importantly, Jak1-deficient stem cells exhibited decreased competitiveness in bone marrow transplantation assays. Flow analysis at 4 weeks post transplantation showed a 3-fold reduced blood chimerism in recipients transplanted with Jak1 KO bone marrow cells and at 16 weeks, Jak1KO cells were largely outcompeted by CD45.1-positive WT cells (Fig. 1c). Jak1-deficient stem cells were also unable to rescue hematopoiesis in the setting of myelosuppressive insults leading to a worse survival of Jak1 KO mice when serially injected with 5-fluorouracil (5-FU) (Fig. 1d). Consistent with the stem cell phenotype observed in JAK1 KO mice, we found that a significant larger proportion of Jak1-deficient stem cells lacks expression of the proliferation marker Ki67 and that Jak1-deficient stem cells fail to enter the cell cycle in response to hematopoietic stress. To begin to determine the mechanism by which Jak1 regulates normal stem cell function in vivo, we assessed the impact of loss of Jak1 on transcriptional output. Gene expression profiling of LT-HSCs from Jak1 KO and WT mice identified 259 significant genes, many of which were known to be Jak1 downstream targets. Gene set enrichment analysis (GSEA) revealed that the majority of genes that were altered following deletion of Jak1 corresponded to interferon signaling and inflammatory response pathways. Consistent with these findings, our functional in vitro and in vivo assays demonstrated that Jak1-deficient cells were insensitive to type I interferons as shown by lack of Stat1 and Stat5 activation (Fig. 1e), retained Sca1 surface expression, and an unchanged cell cycle status upon IFN stimulation. Moreover, the HSC defect observed in the setting of Jak1 loss was not fully rescued by expression of a constitutively active Jak2 allele, suggesting there is non-redundant signaling in HSCs within the JAK kinase family. Together, our data suggests that Jak1 functions as a central node for interferon signaling in HSCs and reveals an essential and nonredundant role of Jak1 in HSC homeostasis and stress response. Figure 1 a) Design of a conditional targeting vector and confirmation of gene deletion on protein level. b) Reduction of LSK cells in Jak1 KO mice. c) Competitive disadvantage of Jak1-deficient cells. d) Increased mortality of Jak1 KO mice when serially challenged with 5-FU. e) Jak1-deficient LSK cells are insensitive to type I interferon stimulation. Figure 1. a) Design of a conditional targeting vector and confirmation of gene deletion on protein level. b) Reduction of LSK cells in Jak1 KO mice. c) Competitive disadvantage of Jak1-deficient cells. d) Increased mortality of Jak1 KO mice when serially challenged with 5-FU. e) Jak1-deficient LSK cells are insensitive to type I interferon stimulation. Disclosures Koppikar: Amgen: Employment. Nolan:Fluidigm: Consultancy. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees.

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Meuwissen, Marije E. C., Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, Scott D. Speer, Zhi Li, et al. "Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome." Journal of Experimental Medicine 213, no. 7 (June 20, 2016): 1163–74. http://dx.doi.org/10.1084/jem.20151529.

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Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

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Li, Peng, Joyce Jing-Yi Wong, Calvin Sum, Wei-Xiang Sin, Kok-Quan Ng, Mickey B. C. Koh, and Keh-Chuang Chin. "IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes." Blood 117, no. 10 (March 10, 2011): 2847–54. http://dx.doi.org/10.1182/blood-2010-07-294272.

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Abstract Robust and rapid induction of interferon-β (IFN-β) in monocytes after pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes. We found that IFN-β was produced rapidly in primary human monocytes as a result of cooperation between the myeloid-specific transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knockdown of IRF8 in monocytes abrogated IFN-β transcription, whereas reintroduction of IRF8 into the IRF8−/− 32Dcl3 murine myeloid cell line reinstated IFN-β transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-β promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-β production, as a previously un-indentified interaction partner of IRF8. We mapped the protein-protein interacting regions of IRF3 and IRF8, and found that their interaction was independent of the DNA-binding domain and the IRF association domain of IRF8 and IRF3, respectively. Therefore, we propose a model for the rapid induction of IFN-β in monocytes, whereby IRF8 and PU.1 form a scaffold complex on the IFN-β promoter to facilitate the recruitment of IRF3, thus enabling rapid IFN-β transcription.

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Balyasnikova, Irina V., Dale A. Pelligrino, John Greenwood, Peter Adamson, Serge Dragon, Hassan Raza, and Elena Galea. "Cyclic Adenosine Monophosphate Regulates the Expression of the Intercellular Adhesion Molecule and the Inducible Nitric Oxide Synthase in Brain Endothelial Cells." Journal of Cerebral Blood Flow & Metabolism 20, no. 4 (April 2000): 688–99. http://dx.doi.org/10.1097/00004647-200004000-00006.

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The authors studied whether cyclic AMP (cAMP), a widespread regulator of inflammation, modulates the cytokine-mediated expression of the intercellular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and the inflammatory nitric oxide synthase 2 (NOS-2), in primary and immortalized brain endothelial cell cultures (GP8.3 cell line). When measured by enzyme-linked immunosorbent assay (ELISA), ICAM-1 was constitutively expressed and was upregulated twofold by interleukin-1β, with no effect of interferon-γ. The NOS-2 activity, assessed by nitrite accumulation, was absent from untreated cultures but was induced by interleukin-1β and interferon-γ acting synergistically. Stimulation of cAMP-dependent pathways with forskolin or dibutyryl cAMP decreased ICAM-1 protein expression, whereas it increased NOS-2 protein expression. For both ICAM-1 and NOS-2, mRNA expression correlated with protein expression. Blockade of NOS activity with L-N-monomethylargiuine (L-NMMA) did not alter ICAM-1 expression, indicating that the nitric oxide released by NOS-2 did not cause the down-regulation of ICAM-1. Analysis of NFκB activation indicated that cAMP acted through a mechanism other than inhibition of nuclear translocation of NFκB. The authors conclude that cAMP modulates the expression of proinflammatory molecules in brain endothelium. This suggests that inflammatory processes at the blood-brain barrier in vivo may be regulated by perivascular neurotransmitters via cAMP.

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Zika, Eleni, Susanna F. Greer, Xin-Sheng Zhu, and Jenny P. Y. Ting. "Histone Deacetylase 1/mSin3A Disrupts Gamma Interferon-Induced CIITA Function and Major Histocompatibility Complex Class II Enhanceosome Formation." Molecular and Cellular Biology 23, no. 9 (May 1, 2003): 3091–102. http://dx.doi.org/10.1128/mcb.23.9.3091-3102.2003.

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ABSTRACT The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-γ) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-γ-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-γ- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs.

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Hasan, Maroof, Vijay K. Gonugunta, Nicole Dobbs, Aktar Ali, Guillermo Palchik, Maria A. Calvaruso, Ralph J. DeBerardinis, and Nan Yan. "Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism." Proceedings of the National Academy of Sciences 114, no. 4 (January 9, 2017): 746–51. http://dx.doi.org/10.1073/pnas.1611113114.

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Three-prime repair exonuclease 1 knockout (Trex1−/−) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase–interferon regulatory factor 3 (cGAS–STING–TBK1–IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1−/− background, and many metabolic defects persist in Trex1−/−Irf3−/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1−/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1−/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.

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Greenberg, Elyse Noelani, Michaela Ellen Marshall, Suoqin Jin, Sanan Venkatesh, Morgan Dragan, Lam C. Tsoi, Johann E. Gudjonsson, Qing Nie, Joseph S. Takahashi, and Bogi Andersen. "Circadian control of interferon-sensitive gene expression in murine skin." Proceedings of the National Academy of Sciences 117, no. 11 (March 4, 2020): 5761–71. http://dx.doi.org/10.1073/pnas.1915773117.

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The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factorIFN regulatory factor 7(Irf7),were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lackingBmal1systemically had exacerbated and arrhythmic ISG/Irf7expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day–dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment.

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Carr, Tiffany, Veena Krishnamoorthy, Shuyang Yu, Hai-Hui Xue, Barbara L. Kee, and Mihalis Verykokakis. "The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation." Journal of Experimental Medicine 212, no. 5 (April 20, 2015): 793–807. http://dx.doi.org/10.1084/jem.20141849.

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Invariant natural killer T cells (iNKT cells) are innate-like T cells that rapidly produce cytokines that impact antimicrobial immune responses, asthma, and autoimmunity. These cells acquire multiple effector fates during their thymic development that parallel those of CD4+ T helper cells. The number of Th2-type effector iNKT cells is variable in different strains of mice, and their number impacts CD8 T, dendritic, and B cell function. Here we demonstrate a unique function for the transcription factor lymphoid enhancer factor 1 (LEF1) in the postselection expansion of iNKT cells through a direct induction of the CD127 component of the receptor for interleukin-7 (IL-7) and the transcription factor c-myc. LEF1 also directly augments expression of the effector fate–specifying transcription factor GATA3, thus promoting the development of Th2-like effector iNKT cells that produce IL-4, including those that also produce interferon-γ. Our data reveal LEF1 as a central regulator of iNKT cell number and Th2-type effector differentiation.

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Journal articles on the topic 'Interferon Regulator Faktor 1'

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