Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1

1999 ◽  
Vol 112 (17) ◽  
pp. 2983-2992 ◽  
Author(s):  
A. Puls ◽  
A.G. Eliopoulos ◽  
C.D. Nobes ◽  
T. Bridges ◽  
L.S. Young ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Epstein Barr Virus ◽  
Actin Polymerization ◽  
Interleukin 1 ◽  
Small Gtpase ◽  
Tnf Alpha ◽  
Nf Kappa B ◽  
Necrosis Factor Alpha ◽  
Barr Virus ◽  
Epstein Barr

Cdc42, a Rho-family GTPase, has been implicated in several signal transduction pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear transcription factor kappa B (NF(kappa)B). We report here that exposure of fibroblasts to the inflammatory cytokines tumor necrosis factor (alpha) (TNF(alpha)) and interleukin-1 (IL-1) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Rac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but not activation of JNK or NF(kappa)B. The latent membrane protein 1 of Epstein-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors. When expressed in fibroblasts, LMP1 stimulates Cdc42-dependent filopodia formation as well as JNK and NF(kappa)B activation. Using LMP1 mutants, we show that activation of Cdc42 and JNK/NF(kappa)B occur through distinct pathways and that Cdc42 activation is independent of LMP1's interaction with TRADD and TRAF proteins.

Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines

1990 ◽  
Vol 10 (2) ◽  
pp. 561-568
Author(s):  
H Shimizu ◽  
K Mitomo ◽  
T Watanabe ◽  
S Okamoto ◽  
K Yamamoto
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Interleukin 6 ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Necrosis Factor Alpha ◽  
Mediators Of Inflammation

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-alpha despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-kappa B transcription factor-binding motifs and binds an IL-1-TNF-alpha-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-kappa B. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-alpha in vivo. These results indicate that a nuclear factor indistinguishable from NF-kappa B is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-alpha.

scholarly journals Establishment and characterization of an Epstein-Barr virus transformed cell line with strong phagocytic activity

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 430-436 ◽  
Author(s):  
P von den Driesch ◽  
R Bhardwaj ◽  
HD Flad ◽  
DC Neugebauer ◽  
HJ Pielken ◽  
...  
Keyword(s):  
Cell Line ◽  
Phagocytic Activity ◽  
Antigen Processing ◽  
Epstein Barr Virus ◽  
Interleukin 1 ◽  
Immunoglobulin M ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Transformed Cell Line ◽  
Epstein Barr

Abstract An immunoglobulin M (IgM)-positive cell line, Ms 28, apparently spontaneously transformed by Epstein-Barr virus (EBV) was established from peripheral blood cells of a patient with immature myeloblastic leukemia. It has been characterized according to phenotype, cytochemistry, and membrane antigen pattern. The cell line expresses lymphoid markers like CD 19, CD 22, and CD 30 and synthesizes and secretes IgM. Monocyte markers CD 11c, CD 14, and CD 15 are absent. Neither interleukin-1 (IL-1), nor tumor necrosis factor (TNF-alpha) are produced. But Ms 28 cells show strong phagocytic activity and engulf Latex particles and sheep RBCs (SRBCs) that need not to be opsonized. The phagocytic activity can be inhibited by chloroquine. Both phagocytosis and EBV nuclear-antigen (EBNA) expression can be observed in one and the same cell. Ms 28 cells might be useful to study immunologic activities like antigen processing and presentation.

scholarly journals Epstein–Barr virus BDLF2–BMRF2 complex affects cellular morphology

2009 ◽  
Vol 90 (6) ◽  
pp. 1440-1449 ◽  
Author(s):  
Jens-Bernhard Loesing ◽  
Stefano Di Fiore ◽  
Klaus Ritter ◽  
Rainer Fischer ◽  
Michael Kleines
Keyword(s):  
Plasma Membrane ◽  
Golgi Apparatus ◽  
Actin Cytoskeleton ◽  
Epstein Barr Virus ◽  
Active Form ◽  
Small Gtpase ◽  
Cellular Morphology ◽  
Subcellular Compartment ◽  
Barr Virus ◽  
Epstein Barr

Herpesvirus glycoproteins often form specific heterodimers that can fulfil functions that cannot be carried out by either of the partners acting alone. This study showed that interactions between the Epstein–Barr virus (EBV) multi-spanning transmembrane envelope protein BMRF2 and type II membrane protein BDLF2 influence the way in which these proteins are trafficked in the cell, and hence the subcellular compartment in which they accumulate. When expressed transiently in mammalian cells, BDLF2 accumulated in the endoplasmic reticulum (ER), whereas BMRF2 accumulated in the ER and Golgi apparatus. However, when the two proteins were co-expressed, BDLF2 was transported with BMRF2 to the Golgi apparatus and from there to the plasma membrane, where the proteins co-localized extensively. The distribution of the two proteins at the plasma membrane was reproducibly associated with dramatic changes in cellular morphology, including the formation of enlarged membrane protrusions and cellular processes whose adhesion extremities were organized by the actin cytoskeleton. A dominant-active form of the small GTPase RhoA was epistatic to this morphological phenotype, suggesting that RhoA is a central component of the signalling pathway that reorganizes the cytoskeleton in response to BDLF2–BMRF2. It was concluded that EBV produces a glycoprotein heterodimer that induces changes in cellular morphology through reorganization of the actin cytoskeleton and may facilitate virion spread between cells.

scholarly journals Epstein-Barr virus modulates de novo protein synthesis in human neutrophils

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2789-2798 ◽  
Author(s):  
AD Beaulieu ◽  
R Paquin ◽  
J Gosselin
Keyword(s):  
Protein Synthesis ◽  
Host Response ◽  
Epstein Barr Virus ◽  
Rna Synthesis ◽  
De Novo ◽  
Interleukin 1 ◽  
Human Neutrophils ◽  
Two Dimensional Gel Electrophoresis ◽  
Barr Virus ◽  
Epstein Barr

Neutrophils and macrophages represent the first line of defense against microbial invaders. However, the role of phagocytes in host response to viral infection is poorly understood. We have previously shown that Epstein-Barr virus (EBV) interacts with human monocytes and modulates cytokine production in this cell type, but its effects on neutrophils are still unknown. In the present study, we investigated the presence of EBV receptor (CR2 or CD21) on neutrophils by cytofluorometry using five different anti-CD21 monoclonal antibodies (MoAbs), as well as fluoroscein isothiocyanate-EBV (FITC-EBV). Whereas no significant amount of neutrophils reacted with anti-CD21 MoAbs, studies with FITC-EBV indicated that viral particles bind to 30% of cells (in some individuals, EBV binds to more than 50% of neutrophils). This interaction is specific as it was completely inhibited by nonconjugated virus or with labeled virus preincubated with neutralizing MoAbs. After EBV treatment, cellular aggregation was observed in neutrophil cultures, an indication that neutrophils were activated. Although EBV did not induce respiratory burst activity in neutrophils, pretreatment with infectious particles enhanced (priming effect) the fMLP-induced O2-release in neutrophils. Instead of restricting our analysis to specific cytokine genes, we investigated the effects of EBV on neutrophil transcriptional events in general. The effect of this virus on de novo synthesis of total cellular RNA was first investigated by measuring the incorporation of [5–3H] uridine into total RNA. The results showed that RNA synthesis in neutrophils was significantly increased (2.3- to 21.3-fold) by EBV compared with the unstimulated controls. Live and UV-inactivated virus markedly induced RNA synthesis, whereas heat-inactivated virus lost this ability. Induction of RNA transcription was EBV specific, as an EBV-neutralizing antiserum abolished this effect. Induction of protein synthesis was also studied by measuring the incorporation of [35S] methionine and [35S] cysteine into secreted and intracellular proteins in neutrophils incubated with EBV. The synthesis of both secreted and cytoplasmic proteins was induced by EBV. One- and two-dimensional gel electrophoresis analysis showed that EBV modulates protein synthesis, because activation of the synthesis of certain proteins was accompanied by the inhibition of others. Interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) synthesis was found to be induced by EBV. Therefore, modulation of host-response proteins such as IL-1Ra could be one of the many mechanisms by which this virus avoids rejection.(ABSTRACT TRUNCATED AT 400 WORDS)

An Epstein-Barr virus-transformed B cell line produces autoregulatory interleukin-1 that regulates bone remodeling

1989 ◽  
Vol 1012 (1) ◽  
pp. 57-63
Author(s):  
Shigemasa Hanazawa ◽  
Shigeru Amano ◽  
Akiei Hamano ◽  
Hideo Katoh ◽  
Teturo Honda ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Bone Remodeling ◽  
Epstein Barr Virus ◽  
Interleukin 1 ◽  
Barr Virus ◽  
Epstein Barr
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