77 results found
Uriz-Huarte A, Date A, Ang H, et al., 2020, The transcriptional repressor REV-ERB as a novel target for disease, Bioorganic & Medicinal Chemistry Letters, Vol: 30, Pages: 127395-127395, ISSN: 0960-894X
REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the regulation of many physiological processes, from circadian rhythm, to immune function and metabolism. Accordingly, REV-ERB has been considered as a promising, but difficult drug target for the treatment of numerous diseases. Here, we concisely review current understanding of the function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chemistry of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target.
Rätsep MT, Moore SD, Jafri S, et al., 2018, Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency., Am J Physiol Lung Cell Mol Physiol, Vol: 315, Pages: L977-L990
Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3-/- mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.
Rollings CM, Sinclair LV, Brady HJM, et al., 2018, Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs, SCIENCE SIGNALING, Vol: 11, ISSN: 1945-0877
Kostrzewski T, Borg AJ, Meng Y, et al., 2018, Multiple levels of control determine how E4bp4/Nfil3 regulates NK cell development, Journal of Immunology, Vol: 200, Pages: 1370-1381, ISSN: 0022-1767
The transcription factor E4bp4/Nfil3 has been shown to have a critical role in the development of all innate lymphoid cell types including NK cells. In this study, we show that posttranslational modifications of E4bp4 by either SUMOylation or phosphorylation have profound effects on both E4bp4 function and NK cell development. We examined the activity of E4bp4 mutants lacking posttranslational modifications and found that Notch1 was a novel E4bp4 target gene. We observed that abrogation of Notch signaling impeded NK cell production and the total lack of NK cell development from E4bp4−/− progenitors was completely rescued by short exposure to Notch peptide ligands. This work reveals both novel mechanisms in NK cell development by a transcriptional network including E4bp4 with Notch, and that E4bp4 is a central hub to process extrinsic stimuli.
Male V, Brady HJM, 2017, Murine thymic NK cells: a case of identity, European Journal of Immunology, Vol: 47, Pages: 797-799, ISSN: 0014-2980
Just over a decade ago, it was established that NK cells in the thymus do not follow precisely the same developmental pathway as conventional NK cells that develop in the bone marrow. Subsequently, it has emerged that NK cells are one branch of a family of innate lymphoid cells (ILCs). ILC1s and thymic NK cells have, however, sufficient similarities such that questions have been raised about how distinctive each cell type is from the other. In this issue of European Journal of Immunology, Gabrielli et al. [Eur. J. Immunol. 2017. 47: 800–805] make a detailed study of the transcription factor requirements of murine thymic NK cells. They provide a valuable insight into the distinctive identity of thymic NK cells with regard to Tbet, Nfil3, Id2, and Ets1. In addition, they clarify the nature of DX5 expression on NK cells and ILC‐like cells in the murine thymus.
Smyth LA, Meader L, Xiao F, et al., 2017, Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance, Clinical and Experimental Immunology, Vol: 188, Pages: 219-225, ISSN: 1365-2249
Anti-apoptotic genes, including those of the Bcl-2 family, have been shown to have dual functionality inasmuch as they inhibit cell death but also regulate inflammation. Several anti-apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation; however, their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl-1), a Bcl-2 family member, under the control of the human intercellular adhesion molecule 2 (ICAM-2) promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the proinflammatory cytokine tumour necrosis factor (TNF)-α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8(+) T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which may be related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti-apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.
Lee B-C, Kim M-S, Pae M, et al., 2016, Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity, Cell Metabolism, Vol: 23, Pages: 685-698, ISSN: 1932-7420
Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4+/− mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4−/− mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNFα, and thereby contribute to the development of obesity-induced insulin resistance.
Boulenouar S, Doisne J-M, Sferruzzi-Perri A, et al., 2016, The residual innate lymphoid cells in nfil3-deficient mice support suboptimal maternal adaptations to pregnancy, Frontiers in Immunology, Vol: 7, ISSN: 1664-3224
Doisne J-M, Balmas E, Boulenouar S, et al., 2015, Composition, Development, and Function of Uterine Innate Lymphoid Cells, Journal of Immunology, Vol: 195, Pages: 3937-3945, ISSN: 0022-1767
Innate lymphoid cells (ILCs), including NK cells, contribute to barrier immunity and tissue homeostasis. In addition to the role of uterine NK cells in placentation and fetal growth, other uterine ILCs (uILCs) are likely to play roles in uterine physiology and pathology. In this article, we report on the composition of uILCs in the endometrium during the luteal phase and in the decidua during early pregnancy. Whereas nonkiller uILC1s and uILC2s are barely detectable in mouse and not detected in humans, a sizeable population of uILC3s is found in human endometrium and decidua, which are mostly NCR+ and partially overlap with previously described IL-22–producing uterine NK cells. Development of mouse uILC3 is Nfil3 independent, suggesting unique features of uILCs. Indeed, although the cytokine production profile of mouse uILCs recapitulates that described in other tissues, IL-5, IL-17, and IL-22 are constitutively produced by uILC2s and uILC3s. This study lays the foundation to understand how ILCs function in the specialized uterine mucosa, both in tissue homeostasis and barrier immunity and during pregnancy.
Kostrzewski T, Brady HJM, 2015, ILC Lineage Specification: To Be or Not 11b, That Is the Question, IMMUNITY, Vol: 43, Pages: 220-222, ISSN: 1074-7613
Xu W, Domingues RG, Fonseca-Pereira D, et al., 2015, NFIL3 Orchestrates the Emergence of Common Helper Innate Lymphoid Cell Precursors, CELL REPORTS, Vol: 10, Pages: 2043-2054, ISSN: 2211-1247
Male V, Nisoli I, Kostrzewski T, et al., 2014, The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression, Journal of Experimental Medicine, Vol: 211, Pages: 635-642, ISSN: 1540-9538
The transcription factor E4bp4 (Nfil3) is essential for natural killer (NK) cell production. Here, we show that E4bp4 is required at the NK lineage commitment point when NK progenitors develop from common lymphoid progenitors (CLPs) and that E4bp4 must be expressed at the CLP stage for differentiation toward the NK lineage to occur. To elucidate the mechanism by which E4bp4 promotes NK development, we identified a central core of transcription factors that can rescue NK production from E4bp4−/− progenitors, suggesting that they act downstream of E4bp4. Among these were Eomes and Id2, which are expressed later in development than E4bp4. E4bp4 binds directly to the regulatory regions of both Eomes and Id2, promoting their transcription. We propose that E4bp4 is required for commitment to the NK lineage and promotes NK development by directly regulating the expression of the downstream transcription factors Eomes and Id2.
Crotta S, Gkioka A, Male V, et al., 2014, The Transcription Factor E4BP4 Is Not Required for Extramedullary Pathways of NK Cell Development, JOURNAL OF IMMUNOLOGY, Vol: 192, Pages: 2677-2688, ISSN: 0022-1767
NK cells contribute to antitumor and antiviral immunosurveillance. Their development in the bone marrow (BM) requires the transcription factor E4BP4/NFIL3, but requirements in other organs are less well defined. In this study, we show that CD3−NK1.1+NKp46+CD122+ NK cells of immature phenotype and expressing low eomesodermin levels are found in thymus, spleen, and liver of E4BP4-deficient mice, whereas numbers of mature, eomesoderminhigh conventional NK cells are drastically reduced. E4BP4-deficient CD44+CD25− double-negative 1 thymocytes efficiently develop in vitro into NK cells with kinetics, phenotype, and functionality similar to wild-type controls, whereas no NK cells develop from E4BP4-deficient BM precursors. In E4BP4/Rag-1 double-deficient (DKO) mice, NK cells resembling those in Rag-1–deficient controls are found in similar numbers in the thymus and liver. However, NK precursors are reduced in DKO BM, and no NK cells develop from DKO BM progenitors in vitro. DKO thymocyte precursors readily develop into NK cells, but DKO BM transfers into nude recipients and NK cells in E4BP4/Rag-1/IL-7 triple-KO mice indicated thymus-independent NK cell development. In the presence of T cells or E4BP4-sufficient NK cells, DKO NK cells have a selective disadvantage, and thymic and hepatic DKO NK cells show reduced survival when adoptively transferred into lymphopenic hosts. This correlates with higher apoptosis rates and lower responsiveness to IL-15 in vitro. In conclusion, we demonstrate E4BP4-independent development of NK cells of immature phenotype, reduced fitness, short t1/2, and potential extramedullary origin. Our data identify E4BP4-independent NK cell developmental pathways and a role for E4BP4 in NK cell homeostasis.
Seillet C, Huntington ND, Gangatirkar P, et al., 2014, Differential Requirement for Nfil3 during NK Cell Development, JOURNAL OF IMMUNOLOGY, Vol: 192, Pages: 2667-2676, ISSN: 0022-1767
Male V, Brady HJM, 2014, Transcriptional Control of NK Cell Differentiation and Function, TRANSCRIPTIONAL CONTROL OF LINEAGE DIFFERENTIATION IN IMMUNE CELLS, Vol: 381, Pages: 173-187, ISSN: 0070-217X
Seillet C, Jackson JT, Markey KA, et al., 2013, CD8 alpha(+) DCs can be induced in the absence of transcription factors Id2, Nfil3, and Batf3, BLOOD, Vol: 121, Pages: 1574-1583, ISSN: 0006-4971
Tong X, Zhang D, Buelow K, et al., 2013, Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 5417-5425
Male V, Nisoli I, Gascoyne DM, et al., 2012, E4BP4: an unexpected player in the immune response, TRENDS IN IMMUNOLOGY, Vol: 33, Pages: 98-102, ISSN: 1471-4906
Lee WH, Salek-Ardakani S, Pandolfi PP, et al., 2012, NPM-MLF1 synergizes with Npm haploinsufficiency to enhance myeloid progenitor activity., Leukemia, Vol: 26(5), Pages: 1110-1112
Martin-Fontecha A, Lord GM, Brady HJM, 2011, Transcriptional control of natural killer cell differentiation and function, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 68, Pages: 3495-3503, ISSN: 1420-682X
de Boer J, Yeung J, Ellu J, et al., 2011, The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors, LEUKEMIA, Vol: 25, Pages: 321-330, ISSN: 0887-6924
Dunne J, Gascoyne DM, Lister TA, et al., 2010, AML1/ETO Proteins Control POU4F1/BRN3A Expression and Function in t(8;21) Acute Myeloid Leukemia, CANCER RESEARCH, Vol: 70, Pages: 3985-3995, ISSN: 0008-5472
Stam RW, Den Boer ML, Schneider P, et al., 2010, Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia, BLOOD, Vol: 115, Pages: 1018-1025, ISSN: 0006-4971
Woodward MJ, de Boer J, Heidorn S, et al., 2010, Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes, CELL DEATH AND DIFFERENTIATION, Vol: 17, Pages: 316-323, ISSN: 1350-9047
Gascoyne DM, Long E, Veiga-Fernandes H, et al., 2009, The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development, NATURE IMMUNOLOGY, Vol: 10, Pages: 1118-U99, ISSN: 1529-2908
Duffin R, Leitch AE, Sheldrake TA, et al., 2009, The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1, FEBS LETTERS, Vol: 583, Pages: 2540-2546, ISSN: 1873-3468
Cao F, Li X, Hiew S, et al., 2009, Dicer independent small RNAs associate with telomeric heterochromatin, RNA, Vol: 15, Pages: 1274-1281, ISSN: 1355-8382
Roig MB, Roset R, Ortet L, et al., 2009, Identification of a novel cyclin required for the intrinsic apoptosis pathway in lymphoid cells, CELL DEATH AND DIFFERENTIATION, Vol: 16, Pages: 230-243, ISSN: 1350-9047
Ruiz A, Williams O, Brady HJM, 2008, The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells, INTERNATIONAL JOURNAL OF CANCER, Vol: 123, Pages: 1240-1245, ISSN: 0020-7136
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