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753 results on '"Ozato, K."'

1. Murine IRF8 Mutation Offers New Insight into Osteoclast and Root Resorption.

Author

Das, A., Yesupatham, S.K., Allison, D., Tanwar, H., Gnanasekaran, J., Kear, B., Wang, X., Wang, S., Zachariadou, C., Abbasi, Y., Chung, M.K., Ozato, K., Liu, C., Foster, B.L., and Thumbigere-Math, V.

Subjects
ROOT resorption (Teeth), BONE resorption, INTERFERON regulatory factors, NUCLEAR factor of activated T-cells, GENETIC mutation, PROTEIN structure
Abstract

Interferon regulatory factor 8 (IRF8), a transcription factor expressed in immune cells, functions as a negative regulator of osteoclasts and helps maintain dental and skeletal homeostasis. Previously, we reported that a novel mutation in the IRF8 gene increases susceptibility to multiple idiopathic cervical root resorption (MICRR), a form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function in osteoclastogenesis, we generated Irf8 knock-in (KI) mice using CRISPR/Cas9 technique modeling the human IRF8 G388S mutation. The heterozygous (Het) and homozygous (Homo) Irf8 KI mice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to wild-type (WT) mice. The Irf8 KI Het and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients, Irf8 KI Het and Homo mice demonstrated significantly increased osteoclast formation and resorption activity in vivo and in vitro when compared to WT mice. The oral ligature–inserted Het and Homo mice displayed significantly increased root resorption and osteoclast-mediated alveolar bone loss compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of IRF8 G388S mutation to inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts, as well as its impact on autophagy-related pathways of osteoclast differentiation. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into the IRF8 mutation associated with MICRR. IRF8 G388S mutation mainly affects osteoclastogenesis while sparing immune cell development and function. These insights extend beyond oral health and significantly advance our understanding of skeletal disorders mediated by increased osteoclast activity and IRF8's role in osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

Author

Morawetz R.A., Giese N.A., Gabriele L., Rothman P., Horak I., Ozato K., and Morse III H.C.

Subjects
ICSBP, immunodeficiency, interferon, MAIDS, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-g, or ICSBP - a transcriptional protein involved in IFN signaling - to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-g is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-g and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs

Published
1998

5. Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Author

Divangahi, M., Aaby, P., Khader, S.A., Barreiro, L.B., Bekkering, S., Chavakis, T., Crevel, R. van, Curtis, N., DiNardo, A.R., Dominguez Andres, J., Duivenvoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K.L., Khan, N., Joosten, L.A.B., Kaufmann, E., Latz, E., Matarese, G., Meer, J.W.M. van der, Mhlanga, M.M.K., Moorlag, S.J.C.F.M., Mulder, W.J.M., Naik, S., Novakovic, B., O'Neill, L., Ochando, J., Ozato, K., Riksen, N.P., Sauerwein, R.W., Sherwood, E.R., Schlitzer, A., Schultze, J.L., Sieweke, M.H., Benn, C.S., Stunnenberg, H., Sun, J, Veerdonk, F.L. van de, Weis, S., Williams, D.L., Xavier, R., Netea, M.G., Divangahi, M., Aaby, P., Khader, S.A., Barreiro, L.B., Bekkering, S., Chavakis, T., Crevel, R. van, Curtis, N., DiNardo, A.R., Dominguez Andres, J., Duivenvoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K.L., Khan, N., Joosten, L.A.B., Kaufmann, E., Latz, E., Matarese, G., Meer, J.W.M. van der, Mhlanga, M.M.K., Moorlag, S.J.C.F.M., Mulder, W.J.M., Naik, S., Novakovic, B., O'Neill, L., Ochando, J., Ozato, K., Riksen, N.P., Sauerwein, R.W., Sherwood, E.R., Schlitzer, A., Schultze, J.L., Sieweke, M.H., Benn, C.S., Stunnenberg, H., Sun, J, Veerdonk, F.L. van de, Weis, S., Williams, D.L., Xavier, R., and Netea, M.G.

Abstract

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Published
2021

13. Idiotypes of anti-Ia antibodies. I. Expression of the 14-4-4S idiotype in humoral immune responses.

Author

Epstein, SL, Ozato, K, Bluestone, JA, and Sachs, DH

Subjects
Biotechnology, Immunization, Vaccine Related, Inflammatory and immune system, Animals, Antibodies, Antibodies, Monoclonal, Antibody Formation, Antibody Specificity, Histocompatibility Antigens Class II, Immunoglobulin Idiotypes, Mice, Mice, Inbred C3H, Medical and Health Sciences, Immunology
Abstract

The idiotype of a mouse monoclonal anti-I-E antibody, 14-4-4S, has been studied using a heterologous anti-idiotypic reagent. This antibody recognizes Ia. 7, an antigenic specificity present in all strains expressing a product of the I-E subregion. Expression of the 14-4-4S idiotype in humoral immune responses was analyzed by an idiotype-specific enzyme-linked immunosorbent assay system. The idiotype was readily detectable in C3H.SW anti-C3H alloantisera, the same immunization combination from which the hybridoma was derived. Absorption analysis demonstrated the anti-I-E specificity of the idiotype-positive molecules in these alloantisera. Penetrance of idiotype expression was high among individual C3H.SW immune mice (9 of 10 tested). To examine genetic requirements for idiotype expression, an immunization was performed using as responders CWB mice, congenic with C3H.SW but differing at the heavy chain allotype loci. Immune sera of individual CWB mice contained very little or no idiotype, demonstrating that levels of idiotype expression are influenced by allotype-linked genes, although the influence of other genes has not been ruled. The 14-4-4S idiotype therefore represents a shared idiotype of anti-Ia antibodies and provides opportunities for analysis of the idiotypes of cellular receptors for the corresponding Ia antigen.

Published
1981

17. Dominant negative retinoid X receptor β inhibits retinoic acid-responsive gene regulation in embryonal carcinoma cells

Author

Minucci, S, Zand, D J, Dey, A, Marks, M S, Nagata, T, Grippo, J F, and Ozato, K

Subjects
Base Sequence, Transcription, Genetic, Receptors, Retinoic Acid, Molecular Sequence Data, Receptors, Cytoplasmic and Nuclear, Cell Differentiation, Tretinoin, DNA, Neoplasm, Cell Biology, Transfection, Gene Expression Regulation, Neoplastic, Mice, Retinoid X Receptors, Genes, Reporter, Carcinoma, Embryonal, Mutation, embryonic structures, Tumor Cells, Cultured, Animals, Molecular Biology, Cell Division, Research Article, DNA Primers, Transcription Factors
Abstract

Retinoid X receptors (RXRs) heterodimerize with multiple nuclear hormone receptors and are thought to exert pleiotropic functions. To address the role of RXRs in retinoic acid- (RA) mediated gene regulation, we designed a dominant negative RXR beta. This mutated receptor, termed DBD-, lacked the DNA binding domain but retained the ability to dimerize with partner receptors, resulting in formation of nonfunctional dimers. DBD- was transfected into P19 murine embryonal carcinoma (EC) cells, in which reporters containing the RA-responsive elements (RAREs) were activated by RA through the activity of endogenous RXR-RA receptor (RAR) heterodimers. We found that DBD- had a dominant negative activity on the RARE reporter activity in these cells. P19 clones stably expressing DBD- were established; these clones also failed to activate RARE-driven reporters in response to RA. Further, these cells were defective in RA-induced mRNA expression of Hox-1.3 and RAR beta, as well as in RA-induced down-regulation of Oct3 mRNA. Gel mobility shift assays demonstrated that RA treatment of control P19 cells induces RARE-binding activity, of which RXR beta is a major component. However, the RA-induced binding activity was greatly reduced in cells expressing DBD-. By genomic footprinting, we show that RA treatment induces in vivo occupancy of the RARE in the endogenous RAR beta gene in control P19 cells but that this occupancy is not observed with the DBD- cells. These data provide evidence that the dominant negative activity of DBD- is caused by the lack of receptor binding to target DNA. Finally, we show that in F9 EC cells expression of DBD- leads to inhibition of the growth arrest that accompanies RA-induced differentiation. Taken together, these results demonstrate that RXR beta and partner receptors play a central role in RA-mediated gene regulation and in the control of growth and differentiation in EC cells.

Published
1994
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20. AB0050 Irf8 Promotes TH17 Differentiation via Activation of Integrin-Mediated Tgfbeta Signaling in Neuroinflammation

Author

Yoshimi, R., primary, Yoshida, Y., additional, Yoshii, H., additional, Kim, D., additional, Dey, A., additional, Xiong, H., additional, Munasinghe, J., additional, Yazawa, I., additional, O'Donovan, M.J., additional, Maximova, O.A., additional, Sharma, S., additional, Zhu, J., additional, Wang, H., additional, Morse, H.C., additional, Ishigatsubo, Y., additional, and Ozato, K., additional

Published
2014
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21. Analysis of estrogenic effects by quantification of green flourescent protein in juvenile fish of a transgenic medaka

Author

Scholz, Stefan, Kurauchi, K., Kinoshita, M., Oshima, Y., Ozato, K., Schirmer, Kristin, Wakamatsu, Y., Scholz, Stefan, Kurauchi, K., Kinoshita, M., Oshima, Y., Ozato, K., Schirmer, Kristin, and Wakamatsu, Y.

Abstract

The ChgH-GFP strain of the teleost medaka contains a regulatory region of the estrogen-responsive choriogenin H (chgH) gene fused to the green fluorescent protein (GFP) gene. The strain was developed for the identification of environmental estrogens by noninvasive analysis of GFP fluorescence. In the present study, a quantification method for GFP by image analysis was established and applied to the analysis of time- and concentration-dependent GFP fluorescence in juvenile fish. Concentration- response analyses were performed with fish exposed for 14 d to 17ß-estradiol (0.37-367 pM), genistein (0.37-367 nM), or p-nonylphenol (0.367-1,835 nM). By means of image analysis, it was shown that ChgH-GFP was induced at 183.5 pM or greater 17ß-estradiol. Time-course and recovery experiments indicated a strong accumulation of GFP in the liver. Results of reverse transcriptase-polymerase chain reaction analysis of choriogenin H and vitellogenin demonstrated induction of gene expression for the same range of concentrations as that for GFP analysis. Neither expression of these genes nor GFP fluorescence was induced by genistein and p-nonylphenol. Although the ChgH-GFP strain failed to detect these weakly estrogenic compounds, the simplicity of the GFP quantification during early life stages of fish offers promising possibilities for further developments of transgenic strains using different target regulatory sequences.

Published
2005

25. Inhibition of estrogen-responsive gene activation by the retinoid X receptor beta: evidence for multiple inhibitory pathways

Author

Segars, J H, Marks, M S, Hirschfeld, S, Driggers, P H, Martinez, E, Grippo, J F, Brown, M, Wahli, W, and Ozato, K

Subjects
Transcriptional Activation, Macromolecular Substances, Receptors, Retinoic Acid, DNA Mutational Analysis, Molecular Sequence Data, Receptors, Cell Surface, In Vitro Techniques, Regulatory Sequences, Nucleic Acid, Structure-Activity Relationship, Tumor Cells, Cultured, Humans, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, Sequence Deletion, Binding Sites, Receptors, Thyroid Hormone, Base Sequence, Nuclear Proteins, Estrogens, Cell Biology, DNA-Binding Proteins, Retinoid X Receptors, Gene Expression Regulation, Oligodeoxyribonucleotides, Receptors, Estrogen, embryonic structures, hormones, hormone substitutes, and hormone antagonists, Research Article, Transcription Factors
Abstract

The retinoid X receptor beta (RXR beta; H-2RIIBP) forms heterodimers with various nuclear hormone receptors and binds multiple hormone response elements, including the estrogen response element (ERE). In this report, we show that endogenous RXR beta contributes to ERE binding activity in nuclear extracts of the human breast cancer cell line MCF-7. To define a possible regulatory role of RXR beta regarding estrogen-responsive transcription in breast cancer cells, RXR beta and a reporter gene driven by the vitellogenin A2 ERE were transfected into estrogen-treated MCF-7 cells. RXR beta inhibited ERE-driven reporter activity in a dose-dependent and element-specific fashion. This inhibition occurred in the absence of the RXR ligand 9-cis retinoic acid. The RXR beta-induced inhibition was specific for estrogen receptor (ER)-mediated ERE activation because inhibition was observed in ER-negative MDA-MB-231 cells only following transfection of the estrogen-activated ER. No inhibition of the basal reporter activity was observed. The inhibition was not caused by simple competition of RXR beta with the ER for ERE binding, since deletion mutants retaining DNA binding activity but lacking the N-terminal or C-terminal domain failed to inhibit reporter activity. In addition, cross-linking studies indicated the presence of an auxiliary nuclear factor present in MCF-7 cells that contributed to RXR beta binding of the ERE. Studies using known heterodimerization partners of RXR beta confirmed that RXR beta/triiodothyronine receptor alpha heterodimers avidly bind the ERE but revealed the existence of another triiodothyronine-independent pathway of ERE inhibition. These results indicate that estrogen-responsive genes may be negatively regulated by RXR beta through two distinct pathways.

Published
1993

26. Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein.

Author

Gabriele, L, Phung, J, Fukumoto, J, Segal, D, Wang, IM, Giannakakou, P, Giese, NA, Ozato, K, Morse, HC, Gabriele, L, Phung, J, Fukumoto, J, Segal, D, Wang, IM, Giannakakou, P, Giese, NA, Ozato, K, and Morse, HC

Abstract

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.

Published
1999

28. A 150-base pair 5' region of the MHC class I HLA-B7 gene is sufficient to direct tissue-specific expression and locus control region activity: the alpha site determines efficient expression and in vivo occupancy at multiple cis-active sites throughout this region.

Author

Kushida, M M, primary, Dey, A, additional, Zhang, X L, additional, Campbell, J, additional, Heeney, M, additional, Carlyle, J, additional, Ganguly, S, additional, Ozato, K, additional, Vasavada, H, additional, and Chamberlain, J W, additional

Published
1997
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35. Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation.

Author

Nelson, N, primary, Kanno, Y, additional, Hong, C, additional, Contursi, C, additional, Fujita, T, additional, Fowlkes, B J, additional, O'Connell, E, additional, Hu-Li, J, additional, Paul, W E, additional, Jankovic, D, additional, Sher, A F, additional, Coligan, J E, additional, Thornton, A, additional, Appella, E, additional, Yang, Y, additional, and Ozato, K, additional

Published
1996
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