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1.
Front Immunol ; 11: 615673, 2020.
Article in English | MEDLINE | ID: mdl-33519824

ABSTRACT

In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology.


Subject(s)
B-Lymphocytes/immunology , Chromatin/genetics , Interferon-gamma/physiology , Lupus Erythematosus, Systemic/metabolism , Phosphatidylinositol 3-Kinases/physiology , Animals , Antibodies, Monoclonal/therapeutic use , Autoantibodies/genetics , Autoantibodies/metabolism , Autoimmunity , B-Lymphocytes/metabolism , DNA Methylation , Disease Models, Animal , Germinal Center/metabolism , Histone Code , Histone Deacetylases/physiology , Humans , Immunoglobulin Class Switching , Lupus Erythematosus, Systemic/drug therapy , Mice , Phosphoric Monoester Hydrolases/metabolism , Plasma Cells/metabolism , Receptors, Interferon/metabolism , Self Tolerance , Interferon gamma Receptor
2.
Mol Cancer Ther ; 16(8): 1680-1692, 2017 08.
Article in English | MEDLINE | ID: mdl-28428441

ABSTRACT

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680-92. ©2017 AACR.


Subject(s)
Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Glucocorticoid/metabolism , Small Molecule Libraries/therapeutic use , Animals , Benzamides , Cell Line, Tumor , Cell Proliferation , Cell Survival , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, Nude , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/metabolism , Signal Transduction , Small Molecule Libraries/pharmacology , Transcription, Genetic
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