The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38. (17/4207)

Human CD38 is a 45-kDa type II membrane glycoprotein with an intricate pattern of expression in leukocytes, although evidence is accumulating of its quite widespread expression in cells of nonvascular origin. CD38 is a member of a nascent eukaryotic gene family encoding cytosolic and membrane-bound enzymes whose substrate is NAD, a coenzyme ubiquitously distributed in nature. Functionally, CD38 is an eclectic molecule with the ability not only to catalyze but also to signal, to mobilize calcium, and to adhere to itself, to hyaluronan, and to other ligands. Interaction with CD38 on various leukocyte subpopulations has profound though diverse consequences on their life-span, but these effects seem to be independent of the enzymatic activity of the molecule. CD38 challenges our expectations of a surface molecule and we must sift through its many guises to unmask its true nature.  (+info)

The tat protein of HIV-1 induces galectin-3 expression. (18/4207)

Animal lectins play important roles in a variety of biological processes via their recognition of glycoconjugates. Galectin-3 is a beta-galactoside-binding lectin whose expression is associated with various pathological processes including human T lymphotropic virus (HTLV)-I-infection of human T cell lines and human immunodeficiency virus (HIV) infection of T-lymphoblastic Molt-3 cell line. In the case of HIV-infected cells, it has been suggested that the increase in galectin-3 expression could be related to the expression of the viral regulatory gene tat. These results prompt us to perform more extensive analyses of the relationship between galectin-3 and HIV-1 Tat expressions. In this study, we found that Tat protein expression induces an upregulation of galectin-3 in several human cell lines. In co-transfection experiments, the 5'-regulatory sequences of the galectin-3 gene were significantly upregulated by expression vectors encoding the Tat protein. Analysis performed with 5'-regulatory deleted sequences suggested that galectin-3 induction by Tat is dependent on activation of the Sp-1 binding transcription factor.  (+info)

Identification of cord blood dendritic cells as an immature CD11c- population. (19/4207)

Dendritic cells (DC) are the main stimulators of primary T-cell responses and, thus, probably play a role in the immune reactions after stem cell transplantation. Very little is known about DC in cord blood (CB) and about their potential involvement in the low incidence and severity of acute graft-versus-host disease after CB transplantation. Here, CBDC were identified as a HLA-DR+ cell population, lacking the CD3, CD11b, CD14, CD16, CD19, CD34, CD56, and glycophorin A lineage markers (lin). This lin-/HLA-DR+ population represented 0.3% +/- 0.1% (mean +/- SD; range, 0.1% to 0. 6%; n = 15) of CB mononuclear cells, and CB contained 5.4 +/- 3.2 x 10(3) CBDC/mL (1.8 to 13.0 x 10(3); n = 15). CBDC expressed CD4, CD11a, CD18, CD45RA, CD50, CD54, and CD123, but showed no expression of CD1a, CD11c, CD33, CD40, CD45R0, CD80, CD83, and CD86 and only limited expression of CD58, CD102, and CD116. Despite this immature phenotype, immunomagnetically lin--enriched CBDC were potent stimulators of allogeneic CB T cells. As few as 266 +/- 107 (193 to 530; n = 10) lin-/HLA-DR+ CBDC stimulated a significant response. However, CBDC failed to take up protein or peptide antigens. Thus, in CB there is a prevalence of a DC subpopulation, resembling the CD11c- DC identified in tonsils, the so-called plasmacytoid T cells, which may exert a function distinct from the CD11c+ DC subpopulation.  (+info)

Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. (20/4207)

BACKGROUND: The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co-stimulatory molecules, and adhesion molecules was analysed. METHODS: CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. RESULTS: CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. CONCLUSIONS: Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type.  (+info)

Neural cell surface differentiation antigen gp130(RB13-6) induces fibroblasts and glioma cells to express astroglial proteins and invasive properties. (21/4207)

Transient expression of the differentiation and tumor cell surface antigen gp130(RB13-6) characterizes a subset of rat glial progenitor cells susceptible to ethylnitrosourea-induced neurooncogenesis. gp130(RB13-6) is as a member of an emerging protein family of ecto-phosphodiesterases/nucleotide pyrophosphatases that includes PC-1 and the tumor cell motility factor autotaxin. We have investigated the potential role of gp130(RB13-6) in glial differentiation by transfection of three cell lines of different origin that do not express endogenous gp130(RB13-6) (NIH-3T3 mouse fibroblasts; C6 and BT7Ca rat glioma cells) with the cDNA encoding gp130(RB13-6). The effect of gp130(RB13-6) expression was analyzed in terms of overall cell morphology, the expression of glial cell-specific marker proteins, and invasiveness. Transfectant sublines, consisting of 100% gp130(RB13-6)-positive cells, exhibited an altered, bipolar morphology. Fascicular aggregates of fibroblastoid cells subsequently developed into mesh-like patterns. Contrary to the parental NIH-3T3 and BT7Ca cells, the transfectant cells invaded into collagen type I. As shown by immunofluorescence staining of the transfectant sublines as well as of primary cultures composed of gp130(RB13-6)-positive and -negative cells, expression of gp130(RB13-6) induced coexpression of proteins typical for glial cells and their precursors, i.e., glial fibrillary acidic protein, the low affinity nerve growth factor receptor, and the neural proteins Thy-1, Ran-2, and S-100. In accordance with its expression in the immature rat nervous system, gp130(RB13-6) may thus have a significant role in the glial differentiation program and its subversion in neurooncogenesis.  (+info)

Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus. (22/4207)

Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine-sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral-CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action.  (+info)

Post-transcriptional regulation of MyD118 and GADD45 in human lung carcinoma cells during 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalene carboxylic acid-induced apoptosis. (23/4207)

Recently, the novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) has been shown to inhibit cell growth and induce apoptosis in several human carcinoma cell lines. To understand the mechanism of AHPN action, we identified, using the differential display method, several genes that are differentially regulated by AHPN. The sequence of one of these genes was highly homologous to mouse MyD118, a gene closely related to GADD45. Both of these genes have been reported to play a role in negative growth control and apoptosis. hMyD118 was expressed in a variety of tissues, including liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, and peripheral blood leukocytes. The levels of both hMyD118 and GADD45 mRNA was rapidly increased in a number of carcinoma cell lines after treatment with AHPN. This increase was specific for AHPN because retinoic acid, a retinoic acid receptor-selective retinoid, and an retinoid X receptor-selective retinoid were ineffective. These results suggest that this action of AHPN involves a novel mechanism that is independent of the nuclear retinoid receptors. AHPN increases the half-life of hMyD118 and GADD45 mRNA by >9-fold, indicating that it causes an increase in the stability of these mRNAs. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoro-methylketone (ZVAD. fmk) had no effect on the induction of hMyD118, indicating that this increase occurred independently of caspase activation. Our study demonstrates that the inhibition of cell growth by AHPN is accompanied by an increase in hMyD118 and GADD45 mRNA, and that this enhancement is regulated at a post-transcriptional level. Our results support a role for MyD118 and GADD45 in the negative growth control by AHPN.  (+info)

The role of CTLA-4 in the regulation of T cell immune responses. (24/4207)

Over the past few years a great deal of research has examined how T cell-dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4+ and CD8+ T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented.  (+info)