Rosette formation by human T and B lymphocytes in the presence of adrenergic and cholinergic drugs

Summary It was shown that adrenergic drugs, which increase the intracellular levels of cAMP, inhibit the rosette formation by T-lymphocytes, but stimulate the rosettes produced by B-lymphocytes. Cholinergic drugs, which increase the levels of cGMP, on the contrary, stimulate the formation of rosettes by T-lymphocytes but inhibit those produced by B-lymphocytes.Acknowledgments. This investigation was supported by Grant from National Council for Scientific and Technological Development (CNPq), Rio de Janeiro, Brazil.     

The influence of sodium-8-chlorotheophyllinate (S8CT) on immune processes

Summary S8CT injected at the time of immunization significantly enhances specific IgM-production but has no effect on IgG-formation. Mitogen (PHA-P) induced macrophage migration inhibition of cells of S8CT pretreated animals is reduced. The same effect is observed, when normal cells are tested in the presence of S8CT in vitro. Blast transformation of B-lymphocytes but not of thymocytes is significantly stimulated by S8CT. Acid phosphatase activity is also stimulated in B-cells and- to a lesser degree-in cortisone-resistant T-lymphocytes whereas the activity of the total thymocyte population is reduced. No effect was seen on phagocytosis and intracellular bactericidal activity. A stimulatory effect of S8CT for B-cells is postulated.Presented in part at the Xth International Congress of Allergology and Clinical Immunology, Jerusalem/Israel 1979, Nov. 4–11.     

Comparison of protein synthesis profiles in chronic lymphocytic leukaemia cells and B-lymphocytes from peripheral blood,cord blood and tonsil

2D-gel electrophoresis was used to investigate protein synthesis in leukaemic cells from a series of 15 chronic lymphocytic leukaemia (CLL) patients, and in non-malignant B-cell populations from different sources. The protein synthesis profiles of CD5+ B-cells from umbilical cord blood and from tonsil were determined, and the levels of expression of their proteins were observed to be similar to the CLL cells. The CD5-cells from cord blood resembled peripheral blood B-lymphocytes, and the protein synthesis profile of CD5-cells from tonsils was very complex. One protein was also identified which consistently appeared to be synthesised at a low level in CD5+ B-cells from tonsil but which was always more prominant in CLL cells and other non-malignant B-lymphocytes. On the basis of these data it is possible that the closest non-malignant counterpart to CLL is the CD5+ B-lymphocyte from cord blood.     

The glycerophosphoinositols: cellular metabolism and biological functions

The glycerophosphoinositols are cellular products of phospholipase A₂ and lysolipase activities on the membrane phosphoinositides. Their intracellular concentrations can vary upon oncogenic transformation, cell differentiation and hormonal stimulation. Specific glycerophosphodiester phosphodiesterases are involved in their catabolism, which, as with their formation, is under hormonal regulation. With their mechanisms of action including modulation of adenylyl cyclase, intracellular calcium levels, and Rho-GTPases, the glycerophosphoinositols have diverse effects in multiple cell types: induction of cell proliferation in thyroid cells; modulation of actin cytoskeleton organisation in fibroblasts; and reduction of the invasive potential of tumour cell lines. More recent investigations include their effects in inflammatory and immune responses. Indeed, the glycerophosphoinositols enhance cytokine-dependent chemotaxis in T-lymphocytes induced by SDF-1α-receptor activation, indicating roles for these compounds as modulators of T-cell signalling and T-cell responses.     

Receptors for cytomegaloviruses on the surface of human lymphocytes]

The relationships between cytomegalovirus (CMV) and lymphocytes have already been noted because of: (a) the immunological abnormalities induced by this virus, and (b) activation of latent CMV in the course of lymphocyte reactions associated with anti-histocompatibility antigen immune response. The present work shows that the lymphocyte surface may have specific receptors for CMV. Cultured fibroblasts infected with DMV were incubated with lymphocytes isolated from the blood of human immune subjects. Rosettes defined by the adherence of three or more lymphocytes around a fibroblast were formed in infected preparation while no rosettes were seen with normal control fibroblasts. Approximately 1.2 per cent of lymphocytes were involved in the formation of these rosettes. Rosette formation is inhibited when infected fibroblasts have been incubated with anti-CMV antibodies prior to the addition of lymphocytes.     

Enrichment in spontaneous and complement dependent rosette forming cell populations using ficoll-hypaque gradient centrifugation

Summary Peripheral blood human T (TL) and B (BL) lymphocytes were separated by continuous Ficoll-Hypaque (FH) gradients. BL were found at the 1050 density interfase (70.5% EAC rosettes) with no TL (0% EAC rosettes); while at the 1068 density interfase there was an enrichment of TL (68% E rosettes) with very few BL (8.5% EAC rosettes).     

Stimulation of H+ ion secretion from the isolated mouse stomach by sodium fluoride

Summary The effect of sodium fluoride on H⁺ ion secretion was investigated in the isolated distended mouse stomach. It was found that sodium fluoride on its own caused dose-related stimulation of H⁺ ion secretion. Sodium fluoride did not inhibit H⁺ ion secretion induced by histamine. The possible mechanisms involved are discussed. It is considered that sodium fluoride might stimulate H⁺ ion secretion by causing histamine release and by increasing cyclic AMP formation in the intact gastric mucosa.     

The effect of nifedipine and verapamil on KC1-induced rhythmic contractions of guinea pig ureter in vitro

Addition of KC1 (40 mM) produced rhythmic contractions of guinea-pig ureters in vitro which were unaffected by phentolamine, atropine or tetrodotoxin. KC1 failed to elicit rhythmic contractions of ureters incubated in a Krebs solution with no added Ca++; in these conditions the addition of CaC12 in concentrations of 1.5 mM, or higher, produced rhythmic contractions whose frequency, but not amplitude, was proportional to CaC12 concentration in the bathing medium. EDTA reduced the frequency of KC1-induced rhythmic contractions without affecting their amplitude. Nifedipine and verapamil reduced both the frequency and the amplitude of KC1-induced rhythmic contraction; verapamil was more effective than nifedipine in reducing their amplitude. Urethane reduced the amplitude without significantly affecting the frequency of KC1-induced rhythmic contractions. An increase in the extracellular Ca++ concentration reverted the suppressive effect of all drugs under study. These results suggest that an influx of Ca++ from the extracellular space is responsible for the initiation of KC1-induced rhythmic contractions and is involved in the mechanism(s) which regulates their frequency, but that a separate mechanism regulates their amplitude.     

Cytotoxicity of human T-lymphocytes sensitized by Epstein-Barr virus. Role of HLA antigens at the surface of target cells infected by the virus]

Peripheral T-lymphocytes from patients with infectious mononucleosis are cytotoxic towards target cells from Epstein-Barr virus-genome carrying human lumphoblastoid lines. Thus, these T-cells appear to be sensitized to viral coded determinants. Daudi cells, that carry EBV-genome, but lack HLA antigens are resistant to specific cytolysis in this model. These results suggest direct HLA involvement in the target structure recognized by birus-sensitized cytolytic T-lymphocytes in human.     

The effect of nifedipine and verapamil on KCl-induced rhythmic contractions of guinea pig ureter in vitro

Summary Addition of KCl (40 mM) produced rhythmic contractions of guinea-pig ureters in vitro which were unaffected by phentolamine, atropine or tetrodotoxin.KCl failed to elicit rhythmic contractions of ureters incubated in a Krebs solution with no added Ca⁺⁺; in these conditions the addition of CaCl₂ in concentrations of 1.5 mM, or higher, produced rhythmic contractions whose frequency, but not amplitude, was proportional to CaCl₂ concentration in the bathing medium.EDTA reduced the frequency of KCl-induced rhythmic contractions without affecting their amplitude. Nifedipine and verapamil reduced both the frequency and the amplitude of KCl-induced rhythmic contraction; verapamil was more effective than nifedipine in reducing their amplitude.Urethane reduced the amplitude without significantly affecting the frequency of KCl-induced rhythmic contractions. An increase in the extracellular Ca⁺⁺ concentration reverted the suppressive effect of all drugs under study. These results suggest that an influx of Ca⁺⁺ from the extracellular space is responsible for the initiation of KCl-induced rhythmic contractions and is involved in the mechanism(s) which regulates their frequency, but that a separate mechanism regulates their amplitude.     

Association between pregnancy-associated alpha2-glycoprotein (alpha2-PAG) and mixed leucocyte reaction determinants on the leucocyte surface.

alpha2-PAG is present on the surface on mononuclear blood leucocytes and can be demonstrated predominantly on B-lymphocytes and monocytes. Pretreatment of cells with antibody to alpha2-PAG leads to a marked reduction in Fc-rosette formation. Competitive blocking experiments with specific antisera reveal a particularly close association between alpha2-PAG and MLR (mixed leucocyte reaction) determinants on the cell surface. These findings suggest one mechanism whereby alpha2-PAG may modify cell-mediated immune responses.     

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.     

Structure and function of eukaryotic peptide transporters

The cotransport of protons and peptides is now recognised as a major route by which dietary nitrogen is absorbed from the intestine, and filtered protein reabsorbed in the kidney. Recently, molecular biology has had a very substantial impact on the study of peptide transport, and here we review the molecular and functional information available within the framework of physiology. To this end we consider not only the mammalian peptide transporters and their tissue distribution and regulation but also those from other species (including Caenorhabditis elegans) which make up the proton-dependent oligopeptide transport superfamily. In addition, understanding the binding requirements for transported substrates may allow future design and targeted tissue delivery of peptide and peptidomimetic drugs. Finally, we aim to highlight some of the less well understood areas of peptide transport, in the hope that it will stimulate further research into this challenging yet exciting topic.     

Biological activities of pure prostaglandins

Prostaglandins, the hydroxy unsaturated C20 fatty acids, are found throughout the body and have an equally wide range of biological activities. Prostaglandins are known to: 1) stimulate uterine contraction; 2) inhibit spontaneous contraction of the rabbit uterus; 3) inhibit the respiratory smooth muscle of different animals; 4) lower systemic arterial blood pressure when injected intravenously; 5) stimulate contractions in isolateral segments of intestinal smooth muscle of most species investigated; 6) produce transient sedation when intravenously injected in cats, and 7) inhibit lipolysis induced by catechal amines, corticotrophin, glucagon and thyroid stimulating hormone. The inhibitory and excitatory effects of prostaglandins may each have a physiological importance at different sites. Current state of knowledge of the distribution, metabolism and actions of the prostaglandins is still fragmentary. The functional significance of the prostaglandins is yet to be determined.     

Role of hsp70 in cytokine production

Interleukin-1 and tumor necrosis factor-alpha are potent, multifunctional cytokine mediators of inflammation and immune responses that are produced primarily by activated monocytes and macrophages. Three published papers by different groups have shown that heat shock and chemical stress with heavy metal salts or sulfhydryl reagents, all of which induce the expression of heat shock protein 70 (hsp70), concomitantly inhibit the production of these cytokines in human monocytes and mouse macrophages activated by lipopolysaccharide. These papers are reviewed and discussed in some detail. Other studies suggest that various anti-inflammatory drugs, including acetylsalicyclic acid, auranofin and dexamethasone, can also facilitate HSP expression in macrophages. However, while these studies are interesting, it is clear that not a great deal of work has been done and/or published in this area. Since many pharmaceutical companies are developing cytokine synthesis inhibitors as potential anti-inflammatory drugs, one aim of this article is to emphasize that understanding the molecular mechanism(s) that lead to increased HSP expression and decreased cytokine biosynthesis may assist in achieving this goal.     

Proliferation of primordial germ cells of frogs stimulated by a fraction of granules derived from Rana nigromaculata embryos at the tail-bud stage

A fraction of heavy granules, obtained from embryos of the frog (Rana nigromaculata) at the tail-bud stage by centrifugation at 1700 x g, were shown to stimulate the formation of proliferation of the primordial germ cells not only of the same species but also of a closely related species.     

The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.     

Identification of rho-antigenic determinants on the surface of mouse T-lymphocytes.

A monospecific antiserum has been prepared in rabbits against purified rho-antigen, a 100,000 mol.wt glycoprotein found on the surface of mouse L-cells. This antiserum has been employed to demonstrate the presence of rho-antigenic determinants selectively on the surface of mouse T-, but not B-lymphocytes.     

Respiratory inhibition and reversible fusion of frog blastomeres.

Rotenone and high doses of chloramphenicol, both of which specifically inhibit electron transport between NADH and flavoprotein in the respiratory chain, caused fully separated Rana pipiens blastomeres to refuse, as shown by syncytium counts on embryos reconstructed from serial sections. With chloramphenicol, the effect was completely reversible: re-cleavage and normal development followed drug removal. The blastomere fusion effect was not produced by the succinic dehydrogenase-specific respiratory inhibitor, thenoyltrifluoroacetone, nor by a non-mitochondrial protein synthesis inhibitor, cycloheximide, both of which instead produced simple arrest of cleavage.