Anti-tumor activity of 5-aminoimidazole-4-carboxamide riboside with AMPK-independent cell death in human adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma caused by human T-cell lymphotropic virus type I (HTLV-1). Acadesine or 5-aminoimidazole-4-carboxamide riboside (AICAR) is an AMP-activated protein kinase (AMPK) activator that was recently shown to have tumor suppressive effects on B cell chronic lymphocytic leukemia, but not ATL. This study evaluated the cytotoxic effects of AICAR on ATL-related cell lines and its anti-tumor activity.

CDK9 Inhibitor Induces Apoptosis, Autophagy, and Suppression of Tumor Growth in Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a hematopoietic malignancy with a poor prognosis that develops in approximately 5% of human T-cell leukemia virus type 1 (HTLV-1) carriers. Cyclin-dependent kinase 9 (CDK9), together with Cyclin T, forms a transcription elongation factor, positive transcription elongation factor b (P-TEFb). P-TEFb promotes transcriptional elongation by phosphorylating the second serine (Ser2) of the seven amino acid repeat sequence in the C-terminal domain of RNA polymerase II (RNAP II).

SRT1720 induces SIRT1-independent cell death in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) develops after a long period of human T-cell leukemia virus (HTLV)-1 infection and is associated with host aging in addition to genetic abnormalities in HTLV-1 infected cells. SIRT1 is a histone deacetylase involved in cell cycle and apoptosis. We previously showed the high expression of SIRT1 protein in peripheral blood mononuclear cells from patients with ATL.

ARP-1 Regulates the Transcriptional Activity of the Aromatase Gene in the Mouse Brain.

An important function of aromatase in the brain is conversion of testosterone secreted from the testis into estradiol. Estradiol produced in the brain is thought to be deeply involved in the formation of sexually dimorphic nuclei and sexual behavior as a neurosteroid. We analyzed the brain-specific promoter to elucidate the control mechanisms of brain aromatase expression that may be highly involved in sexual differentiation of the brain.

Cell death induced by dorsomorphin in adult T-cell leukemia/lymphoma is AMPK-independent.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm with poor prognosis that develops after chronic infection with human T-cell leukemia virus type 1 (HTLV-1). Although AMP-activated protein kinase (AMPK) is a critical cellular energy sensor, it has recently become clear that AMPK can act as a tumor regulator. Here, we assessed the expression of AMPK in primary ATL cells and the effects of dorsomorphin, an AMPK inhibitor, on primary ATL cells and HTLV-1-infected T-cell lines.

Expression and function of DNAM-1 on human B-lineage cells.

Background: Although DNAM-1 is an activating receptor constitutively expressed on the majority of NK cells, CD8 T cells, CD4 T cells, monocytes, and platelets in human, several evidences demonstrated that a small population in B-lineage cells also expressed DNAM-1. However, the expression profile of DNAM-1 on B-lineage cells and its function remain obscure. Previous reports revealed that a considerable number of leukocytes including B cells in the peripheral blood conjugated to platelet.

High expression of NAMPT in adult T-cell leukemia/lymphoma and anti-tumor activity of a NAMPT inhibitor.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1 and has a poor outcome. New molecular targets for the prevention and treatment of ATL are needed urgently. We previously reported high expression of Sirtuin 1, a nicotinamide adenine dinucleotide (NAD)-dependent histone/protein deacetylase, in primary acute-type ATL cells.

Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines.

Background: Sirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide-dependent deacylases, which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Downregulation of SIRT2 using siRNA causes apoptosis of HeLa cells.

The small molecule STF-62247 induces apoptotic and autophagic cell death in leukemic cells.

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required.

Cutting Edge: Identification of Marginal Reticular Cells as Phagocytes of Apoptotic B Cells in Germinal Centers.

Germinal centers (GCs) in secondary lymphoid organs generate large numbers of apoptotic B cells that must be eliminated by phagocytes to prevent the development of autoimmune diseases. Although tingible body macrophages engulf apoptotic GC B cells, whether stromal cells are also involved in this process is unclear. In this study, we identified marginal reticular cells (MRCs) as novel nonprofessional phagocytes for the clearance of apoptotic GC B cells in the spleen.

A pro-inflammatory role of Fcα/μR on marginal zone B cells in sepsis.

Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcγ and Fcε receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors for IgA and IgM, including Fcα/μ receptor (Fcα/μR) (CD351), polymeric immunoglobulin receptor (poly-IgR), Fcα receptor (FcαRI) (CD89) and Fcμ receptor (FcμR).

Improved protocol for the isolation of naïve follicular dendritic cells.

Follicular dendritic cells (FDCs) in lymphoid organs play an important role in the humoral immune response. However, because the isolation of FDCs is difficult due to their very small population size and fragility under mechanical and chemical stresses, the genetic and biochemical characteristics of FDCs remain unclear. Previously, we identified FDCs as ICAM-1 cells in the CD45 non-hematopoietic cell fraction from naïve mouse spleen after cell separation by means of digestion with a combination of enzymes.

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis.

Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling.

Marginal zone (MZ) B cells produce a first wave of antibodies for protection from blood-borne pathogens. However, the role of MZ B cells in inflammatory responses has not been elucidated. Here we show that MZ B cells produce pro-inflammatory cytokines, such as interleukin-6 (IL-6), and exacerbate systemic inflammatory responses to lipopolysaccharide (LPS).

Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces.

Epithelial tissues continually undergo apoptosis. Commensal organisms that inhabit the epithelium influence tissue homeostasis, in which regulatory T cells (Treg cells) have a central role. However, the physiological importance of epithelial cell apoptosis and how the number of Treg cells is regulated are both incompletely understood.

IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor.

Microglia play an important role in receptor-mediated phagocytosis in the CNS. In brain abscess and other CNS infections, invading bacteria undergo opsonization with Igs or complement. Microglia recognize these opsonized pathogens by Fc or complement receptors triggering phagocytosis.

Immune regulation by Fcα/μ receptor (CD351) on marginal zone B cells and follicular dendritic cells.

Although both Fcα/μ receptor (Fcα/μR) and polymeric Ig receptor (poly-IgR) are Fc receptors for IgA and IgM and are functionally and genetically related, the expression profile of Fcα/μR is unique. Unlike poly-IgR, Fcα/μR is expressed on marginal zone (MZ) B cells and follicular dendritic cells, suggesting that Fcα/μR plays an important role in humoral immune responses. Fcα/μR mediates endocytosis of the IgM immune complex (IC).

Novel small-molecule SIRT1 inhibitors induce cell death in adult T-cell leukaemia cells.

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukaemia virus (HTLV)-1. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide(+) -dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis.

CD155 (PVR/Necl5) mediates a costimulatory signal in CD4+ T cells and regulates allergic inflammation.

Although Th1 and Th2 cells are known to be involved in allergic inflammatory diseases, the molecular mechanisms underlying their differentiation are incompletely understood. In this study, we identified CD155 as a costimulatory molecule on CD4(+) T cells. Importantly, CD155-mediated signaling induced Th1 development in both humans and mice, as evidenced by production of IFN-γ and upregulation of Tbx21 transcription; these effects were independent of IL-12 but dependent on NF-κB-induced autocrine IFN-γ that triggered positive feedback via STAT1 activation.

Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters.

Our in vitro characterization showed that physiological concentrations of estrogen partially suppressed the I(Kr) channel current in guinea pig ventricular myocytes and the human ether-a-go-go-related gene (hERG) channel currents in CHO-K1 cells regardless of estrogen receptor signaling and revealed that the partially suppressed hERG currents enhanced the sensitivity to the hERG blocker E-4031. To obtain in vivo proof-of-concept data to support the effects of estrogen on cardiac electrophysiology, we here employed an aromatase knockout mouse as an in vivo estrogen-null model and compared the acute effects of E-4031 on cardiac electrophysiological parameters with those in wild-type mice (C57/BL6J) by recording surface electrocardiogram (ECG). The ablation of circulating estrogens blunted the effects of E-4031 on heart rate and QT interval in mice under a denervation condition.

Anticancer agents targeted to sirtuins.

Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1-7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers.

Increased serum IgA in Fcα/μR-deficient mice on the (129 x C57BL/6) F1 genetic background.

Fcα/μR (CD351) is an Fc receptor for both IgA and IgM, which is abundantly expressed in the small intestine. However, the role of Fcα/μR in the intestinal tissue is largely unknown. Here, we found that Fcα/μR is highly expressed on follicular dendritic cells (FDCs) in Peyer's patches (PP) in the small intestine.

Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration.

Inflammatory monocytes play an important role in host defense against infections. However, the regulatory mechanisms of transmigration into infected tissue are not yet completely understood. Here we show that mice deficient in MAIR-II (also called CLM-4 or LMIR2) are more susceptible to caecal ligation and puncture (CLP)-induced peritonitis than wild-type (WT) mice.

Involvement of Fcα/μR (CD351) in autoantibody production.

Antibody exerts various immune responses via binding to Fc receptors expressed on immune cells. Although several reports have demonstrated that IgM prevents autoantibody production, the role of IgM Fc receptors is largely unknown. To analyze the involvement of Fcα/μR (CD351), an Fc receptor for IgM and IgA expressed on B cells and follicular dendritic cells (FDCs), in IgM-mediated suppression of autoantibody production, we generated mice deficient in Fcα/μR on the background of MRL/MpJ-Fas(lpr/lpr) (Fcamr(-/-)Fas(lpr/lpr)) mice.