Biomedical subjects
S Alkan
Publications and source records attributed to S Alkan.
Transforming growth factor beta 2 differentially modulates interleukin-1 beta- and tumour-necrosis-factor-alpha-stimulated phospholipase A2 and prostaglandin E2 synthesis in rat renal mesangial cells.
Treatment of rat glomerular mesangial cells with transforming growth factor beta 2 (TGF beta 2) stimulates prostaglandin E2 (PGE2) synthesis. Actinomycin D, cycloheximide and diclofenac attenuate the TGF beta 2-induced PGE2 formation. As shown previously, two proinflammatory cytokines, interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha), are potent stimuli for PGE2 and phospholipase A2 secretion from mesangial cells. We report here that, whereas TGF beta 2 potentiates the IL-1 beta- and TNF alpha-evoked PGE2 production, it strongly inhibits the phospholipase A2 secretion induced by both cytokines. In addition, the inhibitory effect of TGF beta 2 on phospholipase A2 secretion is not due to the augmented PGE2 formation.
Chicken growth-associated protein (GAP)-43: primary structure and regulated expression of mRNA during embryogenesis.
Growth-associated protein (GAP)-43 is a neuron-specific phosphoprotein whose expression is associated with axonal outgrowth during neuronal development and regeneration. In order to investigate the expression of this gene product in the early developing nervous system we have isolated and sequenced a cDNA for chicken GAP-43. The predicted amino acid sequence for chicken GAP-43 displays extensive similarity to that of the mammalian protein, particularly in the amino-terminal region, to which functional domains of the protein have been assigned. The cDNA hybridizes with two RNAs of differing molecular weights on Northern blots; both appear to be regulated similarly. These RNAs first appear in the brain on embryonic day 3 (E3), suggesting that GAP-43 begins to be expressed when neuroblasts become post-mitotic. In situ hybridization analysis reveals that GAP-43 RNA is expressed by several neural structures in the chick embryo, including derivatives of the neural tube, neural crest, and neuroectodermal placodes.
Comparison of the immunosuppressive properties of milk growth factor and transforming growth factors beta 1 and beta 2.
The effects of the newly isolated bovine milk growth factor (MGF) which shows N-terminal homology to transforming growth factor beta 2 were compared with the effects of porcine transforming growth factor beta 1 and beta 2 (pTGF-beta 1 and -beta 2) on human T lymphocyte activation. Freshly isolated human PBMC were stimulated with either PHA, anti-CD3 + phorbol-12,13-dibutyrate (PDBu), or with a combination of ionomycin + PDBu. MGF, pTGF-beta 1, and pTGF-beta 2 decreased mitogen-induced [3H]thymidine incorporation by 30 to 75% in a dose-dependent manner. The maximum degree of inhibition was obtained at 1 ng/ml (40 pM) and could not be increased by increasing the concentration of teh transforming growth factor 10-fold. Stimulation of fresh T cells with the recall Ag tetanus toxoid was also inhibited (85%) by MGF at pM concentrations as was the proliferation of a human T cell clone specific for purified protein derivative. The effects of MGF and pTGF-beta 1 on anti-CD3-mediated increase of intracellular Ca2+ (Cai2+) was investigated by using the Fura-2 method. Neither MGF nor pTGF-beta 1 inhibited this increase in Cai2+ induced by a mitogenic concentration of anti-CD3 antibody. In order to determine whether TGF-beta preferentially inhibited the CD4+ or CD8+ subpopulation of human T cells, a limiting dilution analysis system, which allows every T cell to proliferate, was used. pTGF-beta 1 at a concentration of 5 ng/ml decreased the frequency of proliferating T cell precursors of both the CD4+ and CD8+ subsets to a similar extent. Furthermore, MGF, pTGF-beta 1, and pTGF-beta 2 also decreased IL-2 mediated [3H]thymidine incorporation into human PBL Con A blasts and the IL-4-mediated [3H]thymidine incorporation of purified T lymphocytes costimulated with PDBu by 70%. In conclusion, bovine MGF exerts suppressive effects on human T cells stimulated with Ag, mitogens, or interleukins, and the degree of T cell suppression is similar (or identical) to those of pTGF-beta 1 or -beta 2.
Transforming growth factors beta 1 and beta 2 as well as milk growth factor decrease anti-CD3-induced proliferation of human lymphocytes without inhibiting the anti-CD3-mediated increase of [Ca2+]i and the activation of protein kinase C.
Porcine transforming growth factor 1 and 2 (pTGF-beta 1 and -beta 2) and milk growth factor (MGF) at 1 ng/ml significantly inhibited the proliferation of human lymphocytes induced by anti-CD3 antibodies. In contrast, the anti-CD3-mediated increase of intracellular Ca2+ and the activation and translocation of protein kinase C were not affected by the transforming growth factors.
Mediators and the trauma induced cascade of immunologic defects.
Explore the source record for details and available documents.
Alteration of monocyte function following major injury.
The macrophage exerts its stimulatory and regulatory functions within the specific immune response via the interleukin 1 (IL-1) and prostaglandin E2 (PGE2), respectively. In a screening study of macrophage-related variables following injury, a total of 58 patients (mean age, 32 years; mean injury Severity Score, 38), macrophagic phenotyping with the monoclonal antibody Leu M3 and serial measuring of the antagonistic monokines IL-1 and PGE2 and of the macrophage-activating lymphokine interferon gamma were carried out on posttrauma days 0, 1, 3, 5, 7, 10, 14, and 21. The posttraumatic course was characterized by significant monocytosis, showing a peak value of 32% of Leu M3-positive cells compared with 15% of these cells in normal control subjects. During the posttrauma course, the macrophagic PGE2 output was significantly elevated up to eightfold on days 5 and 7 compared with that of control subjects (0.441 +/- 0.14 ng/mL vs 0.052 +/- 0.01 ng/mL). Conversely, macrophagic IL-1 synthesis was significantly suppressed until day 10. Levels of interferon gamma were suppressed to a significant degree during the two-day observation period, with a trend to slow recovery at the end of week 3. These data suggest that a negative regulatory macrophagic function may be the event initiating posttraumatic immunosuppression. To restore impaired macrophagic T-helper cell interaction, cyclo-oxygenase inhibition and substitution of interferon gamma may be useful to potentiate facilitatory macrophagic function and to block inhibitory macrophagic activity.
Murine spleen and lymph node cellular composition and function during cyclophosphamide and splenectomy induced resistance to Toxoplasma gondii.
Murine toxoplasmosis caused by a low virulence, cyst-forming strain of Toxcoplasma gondii (Pe strain) is characterized by splenomegaly, lymphadenopathy, decreased delayed-type hypersensitivity (DTH), and the presence of toxoplasma cysts in brain tissue. Cyclophosphamide (CY) in a single dose of 100 mg/kg injected 3 days before infection, or splenectomy 3 weeks before infection, augmented DTH and decreased the number of toxoplasma brain cysts. CY-induced augmentation of resistance during the first 3 weeks of murine toxoplasmosis was associated with: (1) an increase in mononuclear phagocytes and a decrease in T lymphocytes (including Lyt2+ cells) in spleens and lymph nodes; (2) suppressed toxoplasma antigen induced proliferation of cultured spleen cells: (3) augmentation of antigen induced proliferation of cultured lymph node cells; and (4) low levels of interferon-gamma production in both spleen and lymph node cultures. The best correlate of the enhanced in-vivo effects of CY was proliferation of nylon wool-purified lymph node cells to toxoplasma antigen. The presence of Lyt2+ cells in lymph nodes of toxoplasma infected mice inhibited maximal proliferation.
Structural characterization of syngeneic and allogeneic anti-idiotypic antibodies in the anti-arsonate system.
Explore the source record for details and available documents.
Association of symptomatic human infection with Toxoplasma gondii with imbalance of monocytes and antigen-specific T cell subsets.
During recent symptomatic toxoplasmosis, alterations in quantity and function of mononuclear cells in peripheral blood were observed. Flow cytofluorometric analysis and differential leukocyte counts revealed increased absolute numbers of T8+ cells, Leu 7+ (natural killer/killer) cells, and monocytes. T4+ cells and HLA-DR+ cells were not significantly changed. T4/T8 cell ratios were reversed in symptomatic toxoplasmosis (0.7 +/- 0.3) and normal in chronic infection (1.7 +/- 0.5). Toxoplasma antigen induced higher numbers of T8+ and TQ1+ cells in four T cell lines from two individuals with symptomatic infection than in five T cell lines from three individuals with asymptomatic infection. Eight cloned T cell lines produced gamma interferon in an antigen-specific fashion and in higher amounts when they originated from an asymptomatic subject than from a symptomatic subject. These results indicate that marked alterations in properties of immunoregulatory cells are characteristic of recent symptomatic toxoplasmosis. The transient immune dysfunction may be a major part of the observed disease and/or a feature of successful parasitism.
Spleen and lymph node cell populations, in vitro cell proliferation and interferon-gamma production during the primary immune response to Toxoplasma gondii.
An animal model for the study of transient lymphadenopathy-splenomegaly during toxoplasmosis is presented. Injection of CBA/J mice with the low virulent, cyst-forming strain of Toxoplasma gondii (Pe strain) induces a three to four fold increase in weight and cellularity of spleen and lymph nodes with peak changes at 30-50 days after infection. The spleen displays marked haemopoiesis, a 30 fold increase in mononuclear phagocytes, and a two fold increase in Lyt2+ lymphocytes. Lymph nodes show a five fold increase in mononuclear phagocytes and a four and a half fold increase in Lyt2+ T cells. The increase in mononuclear phagocytes significantly alters T cell/macrophage ratios and this is associated with decreases in in vitro cell proliferation to mitogen and toxoplasma antigen. The relationship between alterations in cell balance of mononuclear phagocytes and T cell subsets and the expression of transient immune dysfunction can now be examined by modulating changes in these cell types.