Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females.
View Article and Find Full Text PDFNeuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis.
View Article and Find Full Text PDFThe severe lymphoproliferative and lupus diseases developed by MRL/ mice depend on interactions between the Fas mutation and MRL genetic background. Thus, the Fas mutation causes limited disease in C57BL/6 mice. We previously found that accumulating B220 CD4CD8 double negative (DN) T cells in MRL/ mice show defective P2X7 receptor ( P2X7)-induced cellular functions, suggesting that P2X7 contributes to T-cell homeostasis, along with Fas.
View Article and Find Full Text PDFWe have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4 and CD8 T cells to ATP depends on their stage of differentiation. Here, we show that CD4 and CD8 T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol.
View Article and Find Full Text PDFHedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production.
View Article and Find Full Text PDFPreviously we reported that the sensitivity of CD4 T cells to ATP does not depend on P2X receptor (P2XR) expression levels but on their activation and differentiation stages. Therefore, here we have investigated a potential relationship between the sensitivity of CD8 T cells to ATP and their stages of differentiation. Thus, the CD8 subpopulation exhibits a drastically reduced sensitivity to ATP with aging, which parallels the strong increase of an effector/memory CD8 subset expressing high levels of CD44 cell adhesion molecule and CD45RB transmembrane phosphatase (CD44CD45RB).
View Article and Find Full Text PDFA previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RB Tconvs, but not CD45RB Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RB Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression.
View Article and Find Full Text PDFP2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors.
View Article and Find Full Text PDFBackground: Arsenic trioxide (As2O3) is highly effective in treating acute promyelocytic leukemia (APL), but shows more variable therapeutic efficacy for other types of hematological malignancies. Previously, we reported that As2O3 selectively eliminates pathogenic B220-expressing T cells in autoimmune MRL/lpr mice. We investigated herein the relationship between As2O3 sensitivity of leukemic T-cell lines and the expression levels of the B220 isoform of transmembrane tyrosine phosphatase CD45.
View Article and Find Full Text PDFDespite much interest in the mechanisms regulating fetal-maternal interactions, information on leukocyte populations and major cytokines present in uterus and placenta remains fragmentary. This report presents a detailed and quantitative study of leukocyte populations at the mouse fetal-maternal interface, including a comparison between pregnancies from syngeneic and allogeneic crosses. Our results provide evidence for drastic differences not only in the composition of leukocyte populations in the uterus during pregnancy, but also between uterine and placental tissues.
View Article and Find Full Text PDFLupus is a chronic inflammatory autoimmune disease influenced by multiple genetic loci including Fas Ligand (FasL) and P2X7 receptor (P2X7R). The Fas/Fas Ligand apoptotic pathway is critical for immune homeostasis and peripheral tolerance. Normal effector T lymphocytes up-regulate the transmembrane tyrosine phosphatase B220 before undergoing apoptosis.
View Article and Find Full Text PDFProtein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-alpha, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-alpha and heparin-binding epidermal growth factor, but Ca++ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17-/- cells. Here, we show that Ca++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17-/- fibroblasts and primary B cells.
View Article and Find Full Text PDFSince 1996, arsenic trioxide (As2O3) is used to treat patients with acute promyelocytic leukemia. We have recently shown that As2O3 is a novel promising therapeutic agent for the autoimmune diseases (human lupus-like syndrome) and the massive lymphoproliferation (human autoimmune lymphoproliferative-like syndrome) developed by MRL/lpr mice. As2O3 is able to achieve an almost complete regression of antibody- and cell-mediated manifestations in MRL/lpr mice.
View Article and Find Full Text PDFMRL/lpr mice develop a human lupuslike syndrome and, as in autoimmune lymphoproliferative syndrome (ALPS), massive lymphoproliferation due to inactivation of Fas-mediated apoptosis. Presently, no effective therapy exists for ALPS, and long term, therapies for lupus are hazardous. We show herein that arsenic trioxide (As2O3) is able to achieve quasi-total regression of antibody- and cell-mediated manifestations in MRL/lpr mice.
View Article and Find Full Text PDFThe Fas/Fas ligand (FasL) pathway is one of the two major effector mechanisms of T cell-mediated cytotoxicity. To prevent nonspecific killing by lymphoid cells, FasL expression on the cell surface of immune effector cells is strictly regulated. However, MRL/lpr autoimmune-prone mice massively overexpress FasL on their T lymphocytes, which render them able to kill Fas+ targets in vitro and in vivo.
View Article and Find Full Text PDFLymphocytes from aged autoimmune MRL/lpr mice overexpress Fas ligand (FasL), and are cytotoxic against Fas+ target cells. This cytotoxic potential is only partly due to FasL, as wild-type MRL+/+ lymphocytes are not able to kill Fas+ targets after induction of FasL. In addition, serum levels of interferon-alpha (IFN-alpha) increase in parallel with the Fas-dependent cytotoxic potential of lymphocytes from MRL/lpr mice as they age.
View Article and Find Full Text PDFArsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL), including those who have relapsed after treatment with all-trans-retinoic acid (RA). In vitro studies with the APL-derived NB4 cell line showed that As2O3 exerts a dose-dependent dual effect, which induces apoptosis at 1 microM, whereas at a lower concentration of 0.1 microM, a partial differentiation of APL is observed.
View Article and Find Full Text PDFLINE-1 are endogenous mobile genetic elements that have dispersed and accumulated in the genomes of eukaryotes via germline transposition, with up to 100,000 copies in mammalian genomes. LINE-1 elements transpose by reverse transcription of their own transcript. Transposition requires synthesis of a full-length, sense-strand transcripts and proteins encoded by open reading frame (ORF) 1 and ORF2.
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