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enric espel

Universitat de Barcelona, Physiology and Immunology, Faculty Member

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Papers by enric espel

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Transcriptional and translational control of TNF‐α gene expression in human monocytes by major histocompatibility complex class II ligands

European Journal of Immunology, 1996

While non‐stimulated primary human monocytes exhibit very low levels of tumor necrosis factor (TN... more While non‐stimulated primary human monocytes exhibit very low levels of tumor necrosis factor (TNF)‐α mRNA, direct binding of the staphylococcal exotoxin toxic shock syndrome toxin‐1 (TSST‐1) to major histocompatibility complex (MHC) class II molecules results in a fast (peak 1 h after stimulation), transient induction (sevenfold) of TNF‐α mRNA. This induction correlates with a fourfold increase in transcription rates of the TNF‐α gene, as detected by run‐on assays, and does not require de novo protein synthesis. Mapping of DNase‐I hypersensitive sites (DHS) discloses two constitutive DHS, one located far upstream (within the TNF‐β promoter) and the other centered at −39 ± 40 bp relative to the major TNF‐α transcription start site, suggesting that the TNF‐α gene was transcriptionally competent even prior to MHC class II engagement. Furthermore, stimulation of human monocytes with either TSST‐1 or lipopolysaccharide increases the translational efficiency of TNF‐α mRNA, as shown by a ...

1 Role of LFA-1 and ICAM-1 in cancer 2

1 Department of Cell Biology, Physiology, Immunology. Faculty of Biology, University of Barcelona... more 1 Department of Cell Biology, Physiology, Immunology. Faculty of Biology, University of Barcelona, Diagonal 4 643. Barcelona 08028, Spain. 5 2 Celltec UB, Faculty of Biology, University of Barcelona, Diagonal 643. Barcelona 08028, Spain. 6 3 Present address: Department of Microbiology and Immunology, Stanford University, Stanford, CA 94121, 7 USA 8 4 Present address: Stanford University School of Medicine, Department of Medicine, Division of 9 Endocrinology, Gerontology, and Metabolism, Stanford, CA 94121, USA 10 * Correspondence: eespel@ub.edu; mreina@ub.edu; Tel.: +34-3-4021630 11 12 13

Anti-proliferative and cytotoxic effect of cannabidiol on human cancer cell lines in presence of serum

BMC Research Notes

Objective Cannabinoids are able to reduce tumor growth in xenograft models, but their therapeutic... more Objective Cannabinoids are able to reduce tumor growth in xenograft models, but their therapeutic potential as anti-cancer drugs in humans is unclear yet. In vitro studies of the effect of cannabinoids on cancer cells are often carried out in absence of serum or in low serum concentration (i.e. 0.5% serum), conditions that limit cellular growth and therefore can increase the response of cells to additional challenges such as the presence of cannabinoids. However, the tumor microenvironment can be teaming with growth factors. In this study we assessed the viability and proliferation of cancer cells treated with cannabidiol in presence of a serum concentration that commonly sustains cell growth (10% serum). Results The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line when cultured in presence of 0.5% serum in comparison to 10% serum, displaying a cytotoxic effect only in the former situation. In presence of 10% serum...

Mouse Interleukin-2 Receptor [IMAGE] Gene Expression

Journal of Biological Chemistry

We have shown that interleukin-1 (IL-1) and IL-2 control IL-2 receptor (IL-2R ) gene transcriptio... more

Role of LFA-1 and ICAM-1 in Cancer

Cancers, Jan 3, 2017

The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and αβ₂), is just ... more The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and αβ₂), is just one of many integrins in the human body, but its significance is derived from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (or CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. We also offer a more detailed examination of the role of LFA-1 within B-cell chronic lymphocytic leukemia. Finally, we discuss the role that exosomes harboring LFA-1 play in tumor growth and metastasis.

Aging, 2017

Absence of ERK5/MAPK7 delays tumorigenesis in <i>Atm</i><sup>-/-</sup> mice

Oncotarget, 2016

Ataxia-telangiectasia mutated (ATM) is a cell cycle checkpoint kinase that upon activation by DNA... more Ataxia-telangiectasia mutated (ATM) is a cell cycle checkpoint kinase that upon activation by DNA damage leads to cell cycle arrest and DNA repair or apoptosis. The absence of Atm or the occurrence of loss-of-function mutations in Atm predisposes to tumorigenesis. MAPK7 has been implicated in numerous types of cancer with prosurvival and pro-growth roles in tumor cells, but its functional relation with tumor suppressors is not clear. In this study, we show that absence of MAPK7 delays death due to spontaneous tumor development in Atm-/mice. Compared with Atm-/thymocytes, Mapk7-/-Atm-/thymocytes exhibited an improved response to DNA damage (increased phosphorylation of H2AX) and a restored apoptotic response after treatment of mice with ionizing radiation. These findings define an antagonistic function of ATM and MAPK7 in the thymocyte response to DNA damage, and suggest that the lack of MAPK7 inhibits thymic lymphoma growth in Atm-/mice by partially restoring the DNA damage response in thymocytes.

Dual role of ERK5 in the regulation of T cell receptor expression at the T cell surface

Journal of Leukocyte Biology, 2015

Regulation of the levels of the TCR/CD3 complex at the cell surface is critical to proper T cell ... more Regulation of the levels of the TCR/CD3 complex at the cell surface is critical to proper T cell development and mature T cell activation. We provide evidence that the MAPK ERK5 regulates the surface expression of the TCR/CD3 complex by controlling the degradation of the CD3ζ chain and the recovery of the complex after anti-CD3ε stimulation. ERK5 knockdown led to TCR/CD3 up-regulation at the cell surface and increased amounts of the CD3ζ chain. Inhibition of the MEK5-dependent phosphorylation status of the kinase domain of ERK5 in human T CD4(+) cells reduced CD3ζ ubiquitination and degradation, limiting TCR/CD3 down-regulation in anti-CD3-stimulated cells. Moreover, TCR/CD3 recovery at the cell surface, after anti-CD3ε treatment, is impaired by ERK5 knockdown or pharmacological inhibition of autophosphorylation in the ERK5 C-terminal region. ERK5 loss in thymocytes augmented cellular CD3ζ and increased cell surface levels of TCR/CD3 on CD4(+)CD8(+) thymocytes. This correlated with enhanced generation of CD4(+)CD8(-)CD25(+) thymocytes. Our findings define ERK5 as a novel kinase that modulates the levels of TCR/CD3 at the cell surface by promoting CD3ζ degradation and TCR/CD3 recovery after TCR stimulation.

Mouse interleukin-2 receptor α gene expression: Interleukin-1 and interleukin-2 control transcription via distinct cis-acting elements

Journal of Biological Chemistry

We have shown that interleukin-1 (IL-1) and IL-2 control IL-2 receptor alpha (IL-2R alpha) gene t... more We have shown that interleukin-1 (IL-1) and IL-2 control IL-2 receptor alpha (IL-2R alpha) gene transcription in CD4-CD8- murine T lymphocyte precursors. Here we map the cis-acting elements that mediate interleukin responsiveness of the mouse IL-2R alpha gene using a thymic lymphoma-derived hybridoma (PC60). The transcriptional response of the IL-2R alpha gene to stimulation by IL-1 + IL-2 is biphasic. IL-1 induces a rapid, protein synthesis-independent appearance of IL-2R alpha mRNA that is blocked by inhibitors of NF-kappa B activation. It also primes cells to become IL-2 responsive and thereby prepares the second phase, in which IL-2 induces a 100-fold further increase in IL-2R alpha transcripts. Transient transfection experiments show that several elements in the promoter-proximal region of the IL-2R alpha gene contribute to IL-1 responsiveness, most importantly an NF-kappa B site conserved in the human and mouse gene. IL-2 responsiveness, on the other hand, depends on a 78-nucl...

Post-transcriptional regulation of TNF-alpha during in vitro differentiation of human monocytes/macrophages in primary culture

Journal of leukocyte biology, 2002

Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, is produced abundantly by mo... more Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, is produced abundantly by monocytes and macrophages. We have compared LPS-stimulated TNF-alpha production and regulation in freshly isolated human monocytes and macrophages differentiated in vitro. A significant increase in LPS-induced TNF-alpha protein secretion was observed in macrophages over freshly isolated monocytes without comparable differences in TNF-alpha mRNA induction. Polysome gradient analysis showed polysome-mRNA distribution did not change, whereas TNF-alpha mRNA stability increased in macrophages. Tristetraprolin mRNA expression was constitutive and decreased with differentiation-linked kinetics. Blockable LPS-inducible MAP kinase activity (p38, ERK) affected TNF-alpha biosynthesis differentially at the transcriptional and post-transcriptional level throughout the culture period. We suggest that the increase in TNF-alpha secretion in macrophages relates to changes in post-transcriptional processing...

Detection by chemical cross-linking of interaction between high mobility group protein 1 and histone oligomers in free solution

The Journal of biological chemistry, Jan 25, 1983

Among the more abundant non-histone proteins is the high mobility group (HMG), with an unknown ro... more Among the more abundant non-histone proteins is the high mobility group (HMG), with an unknown role in chromatin. We have investigated, by chemical cross-linking, the interaction of the protein HMG 1 with the histone dimer H2A X H2B and the histone tetramer (H3 X H4)2 in free solution. Cross-linking with dimethyl suberimidate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and the cleavable cross-linker dimethyl-3,3'-dithiobispropionimidate, by two-dimensional electrophoresis reveals the existence of an interaction between HMG 1 and the histone dimer, and also between HMG 1 and the histone tetramer. In the case of the H2A X H2B dimer, the analysis of the patterns of the cross-linking products shows the presence of a trimer, (H2A X H2B) X HMG 1, and of another oligomer of higher molecular weight which also contains H2A X H2B and HMG 1. Non-histone HMG 1 has been found to interact with (H3 X H4)2, both by cross-linking kinetics and also by gel permeation chromatography, displaying...

Syndecan-2 can promote clearance of T-cell receptor/CD3 from the cell surface

Immunology, 2012

T cells express the heparan sulphate proteoglycans syndecan-2 and syndecan-4. Syndecan-4 plays a ... more T cells express the heparan sulphate proteoglycans syndecan-2 and syndecan-4. Syndecan-4 plays a T-cell inhibitory role; however, the function of syndecan-2 is unknown. In an attempt to examine this function, syndecan-2 was expressed constitutively in Jurkat T cells. Interestingly, the expression of syndecan-2 decreased the surface levels of T-cell receptor (TCR)/ CD3 complex, concomitant with intracellular retention of CD3e and partial degradation of the TCR-ζ chain. Immunofluorescence microscopy revealed that intracellular CD3e co-located with Rab-4 endosomes. However, the intracellular pool of CD3e did not recycle to the cell surface. The lower TCR/CD3 surface levels caused by syndecan-2 led to reduced TCR/ CD3 responsiveness. We show that the cytosolic PDZ-binding domain of syndecan-2 is not necessary to elicit TCR/CD3 down-regulation. These results identify a previously unrecognized means of controlling surface TCR/CD3 expression by syndecan-2.

A Polymorphism in the 3′ Untranslated Region of the Gene for Tumor Necrosis Factor Receptor 2 Modulates Reporter Gene Expression

by Maria Buxadé and enric espel

Endocrinology, 2005

The gene encoding the human TNF␣ receptor (TNFR) 2 contains polymorphisms in the 3 untranslated r... more The gene encoding the human TNF␣ receptor (TNFR) 2 contains polymorphisms in the 3 untranslated region (UTR). Previous studies have shown that some variant alleles in this region are associated with obesity and insulin resistance. However, the effect of these polymorphisms on the expression of TNFR2 has not been studied to date. To examine the role played by different haplotypes in the control of TNFR2 expression (haplotypes A1-A5, referring to nucleotides 1663 G/A, 1668 T/G, and 1690 T/C), we introduced these sequences into the 3-UTR of a heterologous reporter gene and expressed the corresponding constructs in a human T-cell line. We demonstrate that a 485-nt fragment of the TNFR2 3-UTR that contains a U-rich region decreases reporter expression and that haplotypes A1-A4 exert a stronger effect than A5. Furthermore, time-course assays of mRNA stability using actinomycin D revealed that haplotypes A1-A4 destabilize the mRNA. The proximal TNFR2 3-UTR, independently of haplotype differences, responded to T-cell activation by increasing mRNA decay. Electromobility shift analysis demonstrated that protein(s) found in T-cell extracts bind to the 485-nt fragment. We suggest that an increased rate of TNFR2 mRNA decay protects cells from unrestrained TNF␣ effects and that this protection is weakened in A5 subjects. These findings may explain the association of this haplotype with obesity and increased leptin levels. (Endocrinology

Integrating signals from T-cell receptor and serum by T cells enhance translation of tumour necrosis factor-alpha

by Maria Buxadé and enric espel

Immunology, 2001

Tumour necrosis factor-a (TNF-a) is a proin¯ammatory cytokine produced by several cell types, inc... more Tumour necrosis factor-a (TNF-a) is a proin¯ammatory cytokine produced by several cell types, including T cells upon antigen stimulation. Its production is crucial for the development of an early defence against many pathogens, but its bene®cial effects are dependent on the strength and duration of its expression. In this paper we present evidence indicating that serum increases translational ef®ciency of TNF-a in human peripheral blood mononuclear cells stimulated with superantigen. The increase in translation of TNF-a due to serum could be inhibited by the phosphatidylinositol (PI) 3-K inhibitors, wortmannin and LY294002, suggesting that PI 3-K is involved in the translational control of TNF-a by serum. Similarly to primary T cells, stimulation of Jurkat T cells with superantigen led to TNF-a secretion and this was up-regulated by serum. Transfection of Jurkat cells with a constitutively active form of PI 3-Ka increased the production of TNF-a in cells stimulated with superantigen. Additionally, we used the speci®c inhibitors targeting ERK kinase and p38 mitogen-activated protein kinase (MAPK), potentially downstream of PI 3-kinase, PD98059 and SB203580. Differently from with PI 3-K inhibitors, the accumulation of TNF-a mRNA was inhibited by PD98059 or SB203580. These results suggest that, in T cells, activation of PI 3-K is an important step in controlling TNF-a protein synthesis in response to growth factors.

The Mnks Are Novel Components in the Control of TNFα Biosynthesis and Phosphorylate and Regulate hnRNP A1

by Maria Buxadé and enric espel

Immunity, 2005

Posttranscriptional regulatory mechanisms control TNF␣ expression through AU-rich elements in the... more Posttranscriptional regulatory mechanisms control TNF␣ expression through AU-rich elements in the 3UTR of its mRNA. This is mediated through Erk and p38 MAP kinase signaling, although the mechanisms involved remain poorly understood. Here, we show that the MAP kinase signal-integrating kinases (Mnks), which are activated by both these pathways, regulate TNF␣ expression in T cells via the 3UTR. A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNF␣ production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNF␣ 3UTR. We identify ARE binding proteins that are Mnk substrates, such as hnRNP A1, which they phosphorylate at two sites in vitro. hnRNP A1 is phosphorylated in response to T cell activation, and this is blocked by Mnk inhibition. Moreover, Mnk-mediated phosphorylation decreases binding of hnRNP A1 to TNF␣-ARE in vitro or TNF␣-mRNA in vivo. Therefore, Mnks are novel players in cytokine regulation and potential new targets for antiinflammatory therapy.

Wortmannin inhibits translation of tumor necrosis factor- in superantigen-activated T cells

by Maria Buxadé and enric espel

International Immunology, 1999

control of TNF-α translation in human macrophages. In T cells, we have found that the p38 MAPK in... more control of TNF-α translation in human macrophages. In T cells, we have found that the p38 MAPK inhibitor SB 203580 significantly decreased the secretion of TNF-α but not its mRNA. In addition, the combined use of WN and SB 203580 had an additive inhibitory effect on secretion of TNF-α. Therefore, both PI 3-K and p38 MAPK signaling pathways control TNF-α production in T cells.

Corrigendum to “Syndecan-2 and -4 expressed on activated primary human CD4+ lymphocytes can regulate T cell activation” [Mol. Immunol. 45 (10) (2008) 2905–2919]

by Pablo Engel, Trini Teixé, Manuel Reina, and enric espel

Molecular Immunology, 2012

The author regrets that in the above published paper the following error occurred: In of the pape... more The author regrets that in the above published paper the following error occurred: In of the paper cited above, trace amounts of protein A in the affinity chromatography-purified anti-syndecan-2 mAb 186C (protein A which leached from the affinity resin), whose presence went unnoticed, interfered with the anti-CD3 mAb (mouse IgG2a) used to stimulate the T cells. Based on the original results we suggested that syndecan-2 could have an inhibitory effect on T cells. However, reevaluation of similar experiments with protein A-free anti-syndecan-2 mAb 186C indicates that the mAb does not inhibit T-cell proliferation or IL-2 mRNA synthesis.

Use of Western blotting filtration to detect UV-cross-linked protein: RNA complexes

by Trini Teixé and enric espel

Analytical Biochemistry, 2006

Analyses of RNA-protein interactions by UV-crosslinking enable protein:RNA complexes to be charac... more Analyses of RNA-protein interactions by UV-crosslinking enable protein:RNA complexes to be characterized and molecular weights of RNA-binding proteins to be estimated . Sometimes the resulting pattern is unclear, particularly when the RNA-interacting protein is small and migrates close to unbound RNA during gel analysis. Moreover, low-abundance RNA-interacting proteins may not be identiWed because of the noise that occurs in some electrophoretic mobility shift assay (EMSA) 1 patterns. Unbound RNA contributes to this noise. Furthermore, it is diYcult to study the interaction of a puriWed protein with a large RNA molecule (more than 1 kb) using EMSA. RNase digestion of unbound RNA is required in such studies to visualize the protein:RNA complexes formed. Here we outline a method that was Wrst devised for photoaYnity cross-linking [2]. This method simpliWes the characterization of cross-linked protein:RNA complexes. Using the protein-binding capacity of nitrocellulose, protein:RNA complexes can be separated from unbound RNA by Western blotting. This is reminiscent of Wlter binding assays, which are useful for measuring the binding constants of RNA-protein complexes .

Neutralization of Measles Virus Infectivity and Antibody-Dependent Cell-Mediated Cytotoxicity Activity against an Epstein-Barr Virus-Infected Cell Line by Intravenous Immunoglobulin G

by Manuel Reina and enric espel

Clinical and Vaccine Immunology, 2003

Patients with antibody deficiency disorders are highly susceptible to microbial infections. Intra... more Patients with antibody deficiency disorders are highly susceptible to microbial infections. Intravenous (i.v.) immunoglobulin concentrates were originally developed as replacement therapy for such patients. The present study assesses the measles virus neutralizing antibody titers and the antibody-dependent cell-mediated cyto-