Biomedical subjects

T Palkama

Publications and source records attributed to T Palkama.

10 recordsLinked to original sources

PubMed1996

An Epstein-Barr virus-associated superantigen.

More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II-dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta-restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis.

Adult↗

PubMed1994

[Superantigens].

Explore the source record for details and available documents.

Humans↗

PubMed1993

Tyrosine kinase activity is involved in the protein kinase C induced expression of interleukin-1 beta gene in monocytic cells.

The role of protein tyrosine kinases in the expression of interleukin-1 beta (IL-1 beta) gene in response to phorbol esters (PMA) in THP-1 cell line was investigated. Genistein, a specific tyrosine kinase inhibitor, inhibited PMA induced IL-1 beta protein and mRNA levels in THP-1 cells. Genistein did not have a significant effect on PMA induced activity in transient transfection assays using reporter gene constructs containing the PMA responsive sequence of the IL-1 beta gene linked to IL-1 beta promoter, or five repeats of PMA responsive sites (AP-1 sites) in front of a thymidine kinase promoter. This indicates that the tyrosine kinase activity required for the PMA induced IL-1 beta expression is coupled downstream from or functions independent of the PMA induced AP-1 activity.

Cell Line↗

PubMed1993

Signal transduction mechanisms of HLA-DR-mediated interleukin-1 beta production in human monocytes. Role of protein kinase C and tyrosine kinase activation.

The signal transduction pathways leading to the expression of IL-1 beta in human monocytes via HLA-DR stimulation were investigated. SEB, a staphylococcal enterotoxin that binds to HLA-DR molecules, induced IL-1 beta expression in human monocytes. Protein synthesis inhibition by cycloheximide did not inhibit SEB-mediated IL-1 beta signal, indicating that protein synthesis is not required for the MHC class-II-mediated IL-1 beta expression. The effect of PKC, PKA, and tyrosine kinase inhibitors on HLA-DR-mediated IL-1 beta mRNA expression was then determined. H7, a preferential PKC inhibitor, completely inhibited IL-1 beta signal induced by SEB. The role of PKC on HLA-DR-mediated IL-1 beta induction was further confirmed by the ability of SEB to activate PKC on monocytes directly when measured with labeled phorbol ester ([3H]Pbt2)-binding capacity of whole cells. HA 1004, a preferential PKA inhibitor, and isobutyl-methyl-xanthine (IBMX), which inhibits the degradation of cAMP, had no effect on SEB-induced IL-1 beta signal, excluding the role of cAMP on HLA-DR-mediated IL-1 beta expression. Two tyrosine kinase inhibitors, genistein and dihydroxycinnamate, both inhibited SEB-induced IL-1 beta mRNA in monocytes. SEB also induced enhanced tyrosine phosphorylation of several proteins in human monocytes when determined with antiphosphotyrosine immunoblotting. Our results demonstrate that both PKC and protein tyrosine kinases are involved in HLA-DR-induced IL-1 beta expression in human monocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1993

Regulation of endothelial adhesion molecules by ligands binding to the scavenger receptor.

Monocyte adherence to the endothelium, their penetration to the subendothelial space and excessive lipid accumulation (foam cell formation) are the initial events in atherogenesis. Scavenger receptors have been reported to play an important role in foam cell formation, since modified low density lipoproteins can be taken up via scavenger receptors in a non-down-regulated fashion. In this study we demonstrate that stimulation of scavenger receptors in endothelial cells induces the expression of endothelial adhesion molecules. Polyinosinic acid (poly I), a known scavenger receptor ligand, significantly induced the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells when compared with polycytidylic acid (poly C), a structurally related compound to poly I, which does not bind to the scavenger receptor. The effect of scavenger receptor ligands on the endothelial cell line EA hy. 926 was also tested. Poly I up-regulated ICAM-1 expression also on EA hy. 926 cells, while it had no effect on IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) production on the same cell line. Poly I-induced ICAM-1 expression on EA hy. 926 cells could be inhibited by H7, a protein kinase C inhibitor, while HA 1004, a preferential protein kinase A inhibitor, had no effect on ICAM-1 expression. The role of protein kinase C in scavenger receptor-mediated adhesion molecule upregulation was confirmed by the ability of poly I to directly activate protein kinase C, when measured with 3H-phorbol dibutyrate binding to EA hy. 926 cells, while poly C again was ineffective.

Cell Adhesion Molecules↗

PubMed1992

Prolonged elevation of intracellular cyclic AMP activates interleukin-1 production in human peripheral blood monocytes.

The capability of elevated intracellular cyclic AMP concentration to activate IL-1 gene expression and protein production was examined in human peripheral blood monocytes. In accordance with previous studies it was observed that the transiently elevated cyclic AMP (induced either with prostaglandin E2 or with the direct adenylate cyclase activator, forskolin) was not a sufficient signal to activate IL-1 production. However, if the degradation of cyclic AMP was inhibited with isobutyl-methyl-xanthine (IBMX), IL-1 production was strongly activated. This prostaglandin E2 plus IBMX effect could also be mimicked with high concentrations of the cell permeant structural cyclic AMP analogue, dibutyryl cyclic AMP. The cyclic AMP-induced IL-1 production differed in some aspects from the bacterial lipopolysaccharide-induced IL-1 production: (1) the kinetics of both IL-1 gene expression and protein production was much slower; (2) the IL-1 beta gene expression was superinducible by inhibiting the protein synthesis with cycloheximide. Thus these data suggest that prolonged elevation of cyclic AMP is alone a sufficient signal to activate IL-1 production.

Blotting, Northern↗

PubMed1991

Cyclic adenosine monophosphate decreases the secretion, but not the cell-associated levels, of interleukin-1 beta in lipopolysaccharide-activated human monocytes.

Interleukin-1 beta (IL-1 beta) is a cytokine produced mainly by activated monocytes though the mechanism by which it is released is still unknown. Elevation of intracellular cyclic adenosine monophosphate (cAMP) is considered an important down-regulative signal in the production of IL-1 beta in lipopolysaccharide (LPS)-induced monocytes. In this study we show that in LPS-activated human monocytes, elevated cAMP concentrations (induced by either prostaglandin E2, forskolin or dibutyrylcyclic AMP) affected specifically secretion of IL-1 beta; the amount of secreted IL-1 beta was clearly reduced whereas the cell-associated level remained unchanged. TNF-alpha, a normal secretory protein, was used as a control. Cyclic AMP also inhibited TNF production by monocytes, but the decrease was of the same magnitude in the extracellular and intracellular compartments. Thus, the down-regulative effect of cAMP on the production of these monokines is clearly different.

Bucladesine↗

PubMed1991

Induction of interleukin-1 production by ligands binding to the scavenger receptor in human monocytes and the THP-1 cell line.

Foam cell formation via lipid accumulation through the scavenger receptor in human monocyte/macrophages is believed to be one of the earliest events in atherogenesis. In this study we demonstrate that stimulation of the scavenger receptor activates monocytes to produce interleukin-1 (IL-1). Polyinosinic acid (poly I) and fucoidan, both ligands known to bind to the scavenger receptor, induced IL-1 beta production in human monocytes. Polycytidylic acid, a structurally related compound to poly I, which does not bind to the scavenger receptor, was used as a negative control and had virtually no effect on IL-1 production. THP-1 cells, which normally do not express scavenger receptors, were almost unresponsive to poly I and fucoidan. PMA priming, which has been reported to up-regulate scavenger receptor expression in THP-1 cells, significantly enhanced IL-1 production by fucoidan and poly I. IL-1 produced by scavenger receptor stimulation was shown to be secreted extracellularly, and biologically active. Scavenger receptor-mediated IL-1 production was inhibited by H7, a protein kinase C inhibitor, and enhanced by IBMX, an inhibitor of cyclic AMP degradation, suggesting a synergistic effect of protein kinase C and cyclic AMP-mediated signal transduction pathways in scavenger receptor-mediated IL-1 production. Due to the potentially deleterious effects of IL-1 on the vessel wall, IL-1 produced by ligand binding to the scavenger receptor in human monocytes may play a role in the pathogenesis of atherosclerosis.

Cell Line↗

PubMed1989

Induction of interleukin 1 alpha (IL-1 alpha) and IL-1 beta mRNA expression and cellular IL-1 production by anti-HLA-DR antibodies in human monocytes.

We studied the role of HLA class II antigens in the regulation of interleukin 1 (IL-1) production in human monocytes. Monocytes were cultured with monoclonal anti-HLA-DR antibodies for 24 h after which cellular (i.e. intracellular and membrane-associated) IL-1 production, IL-1 secretion, and the expression of IL-1 alpha and IL-1 beta mRNA were determined. One of the anti-HLA-DR antibodies tested (anti-HLA-DR, Becton Dickinson) clearly induced IL-1 alpha and IL-1 beta mRNA expression and cellular IL-1 production. The other anti-HLA-DR antibody tested (OKIa1, Ortho) had no effect on IL-1 production. The stimulatory effect of anti-HLA-DR was enhanced by IFN-gamma in both fresh and aged monocytes. A synergistic effect by anti-HLA-DR and suboptimal doses of LPS (1 ng/ml) on both cellular IL-1 production and secretion was also demonstrated. The possibility of contaminating LPS causing the IL-1-inducing effect of anti-HLA-DR was excluded by the inability of polymyxin B to abolish the anti-HLA-DR-induced IL-1 production.

Adjuvants, Immunologic↗

PubMed1988

Interleukin-4 inhibits interleukin-1 synthesis by a posttranscriptional mechanism.

T cell derived cytokines, interleukin-2 and interferon-gamma, are known to upregulate the interleukin-1 synthesis of monocyte/macrophages. The effect of a third T cell derived cytokine, interleukin-4, was now investigated. Human peripheral blood monocytes were activated with bacterial lipopolysaccharide in the presence or absence of interleukin-4 and the production of biologically active interleukin-1 was quantitated both from the culture supernatants and from the monocyte lysates using the mouse thymocyte assay. Interleukin-4 had a clear dose-dependent suppressive effect on the interleukin-1 synthesis. IL-1 alpha and IL-1 beta mRNA levels, quantitated by Northern blot analysis, were equally high in the lipopolysaccharide plus interleukin-4 supplemented cultures and in the cultures with lipopolysaccharide alone, suggesting that the effect of interleukin-4 in the interleukin-1 biosynthesis is post-transcriptional.

Animals↗