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Spyrou, Giannis
Alternative names
Publications (10 of 75) Show all publications
Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V.-M., . . . Rosén, A. (2018). Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C.. Proceedings of the National Academy of Sciences of the United States of America, 115(3), E478-E487
Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C.
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
Abstract [en]

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences, 2018
Keywords
CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
National Category
Basic Medicine Immunology in the medical area
Research subject
Economic Information Systems
Identifiers
urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)
Funder
Swedish Cancer Society
Note

Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-02-12Bibliographically approved
Nalvarte, I., Damdimopoulos, A. E., Ruegg, J. & Spyrou, I. (2015). The expression and activity of thioredoxin reductase 1 splice variants v1 and v2 regulate the expression of genes associated with differentiation and adhesion. Bioscience Reports, 35(e00269)
Open this publication in new window or tab >>The expression and activity of thioredoxin reductase 1 splice variants v1 and v2 regulate the expression of genes associated with differentiation and adhesion
2015 (English)In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 35, no e00269Article in journal (Refereed) Published
Abstract [en]

The mammalian redox-active selenoprotein thioredoxin reductase (TrxR1) is a main player in redox homoeostasis. It transfers electrons from NADPH to a large variety of substrates, particularly to those containing redox-active cysteines. Previously, we reported that the classical form of cytosolic TrxR1 (TXNRD1_v1), when overexpressed in human embryonic kidney cells (HEK-293), prompted the cells to undergo differentiation [Nalvarte et al. (2004) J. Biol. Chem. 279, 54510-54517]. In the present study, we show that several genes associated with differentiation and adhesion are differentially expressed in HEK-293 cells stably overexpressing TXNRD1_v1 compared with cells expressing its splice variant TXNRD1_v2. Overexpression of these two splice forms resulted in distinctive effects on various aspects of cellular functions including gene regulation patterns, alteration of growth rate, migration and morphology and susceptibility to selenium-induced toxicity. Furthermore, differentiation of the neuroblastoma cell line SH-SY5Y induced by all-trans retinoic acid (ATRA) increased both TXNRD1_v1 and TXNRD1_v2 expressions along with several of the identified genes associated with differentiation and adhesion. Selenium supplementation in the SH-SY5Y cells also induced a differentiated morphology and changed expression of the adhesion protein fibronectin 1 and the differentiation marker cadherin 11, as well as different temporal expression of the studied TXNRD1 variants. These data suggest that both TXNRD1_v1 and TXNRD1_v2 have distinct roles in differentiation, possibly by altering the expression of the genes associated with differentiation, and further emphasize the importance in distinguishing each unique action of different TrxR1 splice forms, especially when studying the gene silencing or knockout of TrxR1.

Place, publisher, year, edition, pages
PORTLAND PRESS LTD, 2015
Keywords
differentiation; migration; oxidative stress; selenium; thioredoxin reductase.
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124654 (URN)10.1042/BSR20150236 (DOI)000368296800005 ()26464515 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2004-5057]; Medical Faculty of Linkoping University

Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2017-11-30
Diamanti, E., Mathieu, S., Jeanneau, C., Kitraki, E., Panopoulos, P., Spyrou, G. & About, I. (2013). Endoplasmic reticulum stress and mineralization inhibition mechanism by the resinous monomer HEMA. International Endodontic Journal, 46(2), 160-168
Open this publication in new window or tab >>Endoplasmic reticulum stress and mineralization inhibition mechanism by the resinous monomer HEMA
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2013 (English)In: International Endodontic Journal, ISSN 0143-2885, E-ISSN 1365-2591, Vol. 46, no 2, p. 160-168Article in journal (Refereed) Published
Abstract [en]

AIM: To investigate the expression of two endoplasmic reticulum (ER)-resident key chaperone proteins, ERdj5 and BiP, under the influence of resinous monomers and its relationship with the inhibition of mineralization caused by the monomer 2-hydroxyethyl methacrylate (HEMA).

METHODOLOGY: The ERdj5 and BiP expression was studied in vitro, in primary human pulp cell cultures after treatment with three different HEMA concentrations at different time periods. Subsequently, the expression of both the odontoblast markers dentine sialoprotein (DSP) and osteonectin (OSN) was studied in human pulp cells under the same conditions.

RESULTS: The ERdj5 and BiP expression was upregulated in the pulp cells. DSP and OSN were largely dispersed in the cytoplasm in control cell cultures but accumulated in a perinuclear area after exposure to HEMA. Their expression levels were not affected.

CONCLUSIONS: The increased expression of ERdj5 and BiP may reflect activation of ER stress. DSP and OSN accumulation into the cells may lead to their secretion arrest and inhibition of dentine matrix formation. These events may elucidate the mechanism by which HEMA inhibits the mineralization process.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
BiP, dentine sialoprotein, endoplasmic, reticulum stress, ERdj5, HEMA, mineralization, osteonectin, resinous monomers.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98785 (URN)10.1111/j.1365-2591.2012.02103.x (DOI)22889382 (PubMedID)
Available from: 2013-10-14 Created: 2013-10-14 Last updated: 2017-12-06Bibliographically approved
Chantzoura, E., Prinarakis, E., Panagopoulos, D., Mosialos, G. & Spyrou, G. (2010). Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling. Biochemical and Biophysical Research Communications - BBRC, 403(3-4), 335-339
Open this publication in new window or tab >>Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling
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2010 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 403, no 3-4, p. 335-339Article in journal (Refereed) Published
Abstract [en]

Glutaredoxin-1 (GRX-1) is a cytoplasmic enzyme that highly contributes to the antioxidant defense system. It catalyzes the reversible reduction of glutathione-protein mixed disulfides, a process called deglutathionylation. Here, we investigated the role of GRX-1 in the pathway triggered by interleukin-1/Toll-like receptor 4 (IL-1R/TLR4) by using RNA interference (RNAi) in HEK293 and HeLa cells. TNF receptor-associated factor 6 (TRAF6) is an intermediate signalling molecule involved in the signal transduction by members of the interleukin-1/Toll-like receptor (IL-1R/TLR) family. TRAF6 has an E3 ubiquitin ligase activity which depends on the integrity of an amino-terminal really interesting new gene (RING) finger motif. Upon receptor activation, TRAF6 undergoes K63-linked auto-polyubiquitination which mediates protein-protein interactions and signal propagation. Our data showed that IL-1R and TLR4-mediated NF-κB induction was severely reduced in GRX-1 knockdown cells. We found that the RING-finger motif of TRAF6 is S-glutathionylated under normal conditions. Moreover, upon IL-1 stimulation TRAF6 undergoes deglutathionylation catalyzed by GRX-1. The deglutathionylation of TRAF6 is essential for its auto-polyubiquitination and subsequent activation. Taken together, our findings reveal another signalling molecule affected by S-glutathionylation and uncover a crucial role for GRX-1 in the TRAF6-dependent activation of NF-κB by IL-1R/TLRs.

Place, publisher, year, edition, pages
Elsevier, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98720 (URN)10.1016/j.bbrc.2010.11.029 (DOI)000286021300015 ()21078302 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06
Thomas, C. G. & Spyrou, G. (2009). ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis. Journal of Biological Chemistry, 284(10), 6282-6290
Open this publication in new window or tab >>ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis
2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 10, p. 6282-6290Article in journal (Refereed) Published
Abstract [en]

Down-regulation of the unfolded protein response (UPR) can be therapeutically valuable in cancer treatment, and endoplasmic reticulum (ER)-resident chaperone proteins may thus be targets for developing novel chemotherapeutic strategies. ERdj5 is a novel ER chaperone that regulates the ER-associated degradation of misfolded proteins through its associations with EDEM and the ER stress sensor BiP. To investigate whether ERdj5 can regulate ER stress signaling pathways, we exposed neuroblastoma cells overexpressing ERdj5 to ER stress inducers. ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells. To provide further evidence that ERdj5 induces ER stress-regulated apoptosis, we targeted Bcl-2 to ER of ERdj5-overexpressing cells. Targeting the Bcl-2 to ER prevented the apoptosis induced by ER stress inducers but not by non-ER stress apoptotic stimuli, suggesting induction of ER stress-regulated apoptosis by ERdj5. ERdj5 enhanced apoptosis by abolishing the ER stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and the subsequent translational repression. ERdj5 was found to inhibit the eIF2alpha phosphorylation under ER stress through inactivating the pancreatic endoplasmic reticulum kinase. The compromised integrated stress response observed in ERdj5-overexpressing ER-stressed cells due to repressed eIF2alpha phosphorylation correlated with impaired neuroblastoma cell resistance under ER stress. These results demonstrate that ERdj5 decreases neuroblastoma cell survival by down-regulating the UPR, raising the possibility that this protein could be a target for anti-tumor approaches.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2009
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98718 (URN)10.1074/jbc.M806189200 (DOI)000263742700031 ()19122239 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06
Psarra, A.-M. G., Hermann, S., Panayotou, G. & Spyrou, G. (2009). Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-κB modulates glucocorticoid receptor and NF-κB signalling in HEK-293 cells. Biochemical Journal, 422(3), 521-531
Open this publication in new window or tab >>Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-κB modulates glucocorticoid receptor and NF-κB signalling in HEK-293 cells
2009 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 422, no 3, p. 521-531Article in journal (Refereed) Published
Abstract [en]

Trx2 (mitochondrial thioredoxin) is an antioxidant and anti-apoptotic factor essential for cell viability. Trx1 (cytoplasmic thioredoxin) is a co-factor and regulator of redox-sensitive transcription factors such as the GR (glucocorticoid receptor) and NF-kappaB (nuclear factor kappaB). Both transcription factors have been detected in mitochondria and a role in mitochondrial transcription regulation and apoptosis has been proposed. In the present study, we show using SPR (surface plasmon resonance) and immunoprecepitation that GR and the p65 subunit of NF-kappaB are Trx2-interacting proteins. The interaction of Trx2 with GR is independent of the presence of GR ligand and of redox conditions. The p65 subunit of NF-kappaB can interact with Trx2 in the oxidized, but not the reduced, form. Using HEK (human embryonic kidney)-293 cell lines with increased or decreased expression of Trx2, we show that Trx2 modulates transcription of GR and NF-kappaB reporter genes. Moreover, Trx2 overexpression modulates the mRNA levels of the COX1 (cytochrome oxidase subunit I) and Cytb (cytochrome b), which are known to be regulated by GR and NF-kappaB. Increased expression of Trx2 differentially affects the expression of Cytb. The glucocorticoid dexamethasone potentiates the expression of Cytb, whereas TNFalpha (tumour necrosis factor alpha) down-regulates it. These results suggest a regulatory role for Trx2 in GR and NF-kappaB signalling pathways.

Place, publisher, year, edition, pages
Portland Press, 2009
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98719 (URN)10.1042/BJ20090107 (DOI)19570036 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06
Damdimopoulos, A. E., Spyrou, G. & Gustafsson, J.-Å. (2008). Ligands differentially modify the nuclear mobility of estrogen receptors alpha and beta. Endocrinology, 149(1), 339-345
Open this publication in new window or tab >>Ligands differentially modify the nuclear mobility of estrogen receptors alpha and beta
2008 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 1, p. 339-345Article in journal (Refereed) Published
Abstract [en]

Signaling of nuclear receptors depends on the structure of their ligands, with different ligands eliciting different responses. In this study using a comparative analysis, an array of ligands was examined for effects on estrogen receptor alpha (ERalpha) and ERbeta mobility. Our results indicated that these two receptors share similarities in response to some ligands but differ significantly in response to others. Our results suggest that for ERalpha, ligands can be classified into three distinct groups: 1) ligands that do not affect the mobility of the receptor, 2) ligands that cause a moderate effect, and 3) ligands that strongly impact mobility of ERalpha. Interestingly, we found that for ERbeta such a classification was not possible because ERbeta ligands caused a wider spectrum of responses. One of the main differences between the two receptors was the response toward the antiestrogens ICI and raloxifene, which was not attributable to differential subnuclear localization or different conformations of helix 12 in the C-terminal domain. We showed that both of these ligands caused a robust phenotype, leading to an almost total immobilization of ERalpha, whereas ERbeta retained its mobility; we provide evidence that the mobility of the two receptors depends upon the function of the proteasome machinery. This novel finding that ERbeta retains its mobility in the presence of antiestrogens could be important for its ability to regulate genes that do not contain classic estrogen response element sites and do not require DNA binding and could be used in the investigation of ligands that show ER subtype specificity.

Place, publisher, year, edition, pages
The Endocrine Society, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98715 (URN)10.1210/en.2007-0198 (DOI)000251797500040 ()17884941 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
Prinarakis, E., Chantzoura, E., Thanos, D. & Spyrou, G. (2008). S-glutathionylation of IRF3 regulates IRF3-CBP interaction and activation of the IFN beta pathway. EMBO Journal, 27(6), 865-875
Open this publication in new window or tab >>S-glutathionylation of IRF3 regulates IRF3-CBP interaction and activation of the IFN beta pathway
2008 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 27, no 6, p. 865-875Article in journal (Refereed) Published
Abstract [en]

Interferon regulatory factor 3 (IRF3) is an essential transcriptional regulator of the interferon genes. IRF3 is constitutively present in a latent conformation in the cell cytoplasm. In cells infected by Sendai virus, IRF3 becomes phosphorylated, homodimerizes, translocates to the nucleus, binds to target genes and activates transcription by interacting with CBP/p300 co-activators. In this study, we report that in non-infected cells IRF3 is post-translationally modified by S-glutathionylation. Upon viral-infection, it undergoes a deglutathionylation step that is controlled by the cytoplasmic enzyme glutaredoxin-1 (GRX-1). In virus-infected GRX-1 knockdown cells, phosphorylation, homodimerization and nuclear translocation of IRF3 were not affected, but the transcriptional activity of IRF3 and the expression of interferon-beta (IFNbeta), were severely reduced. We show that deglutathionylation of IRF3 is necessary for efficient interaction of IRF3 with CBP, an event essential for transcriptional activation of the interferon genes. Taken together, these findings reveal a crucial role for S-glutathionylation and GRX-1 in controlling the activation of IRF3 and IFNbeta gene expression.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98717 (URN)10.1038/emboj.2008.28 (DOI)000254179200005 ()18309294 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
Zhou, J., Eleni, C., Spyrou, G. & Brüne, B. (2008). The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1a protein. Free Radical Biology & Medicine, 44(1), 91-98
Open this publication in new window or tab >>The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1a protein
2008 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 44, no 1, p. 91-98Article in journal (Refereed) Published
Abstract [en]

Hypoxia-inducible factor-1 (HIF-1), consisting of two subunits, HIF-1alpha and HIF-1beta, is a key regulator for adaptation to low oxygen availability, i.e., hypoxia. Compared to the constitutively expressed HIF-1beta, HIF-1alpha is regulated by hypoxia but also under normoxia (21% O(2)) by several stimuli, including nitric oxide (NO). In this study, we present evidence that overexpression of mitochondrial-located thioredoxin 2 (Trx2) or thioredoxin reductase 2 (TrxR2) attenuated NO-evoked HIF-1alpha accumulation and transactivation of HIF-1 in HEK293 cells. In contrast, cytosolic-located thioredoxin 1 (Trx1) enhanced HIF-1alpha protein amount and activity under NO treatments. Taking into consideration that thioredoxins affect the synthesis of HIF-1alpha by altering Akt/mTOR signaling, we herein show that p42/44 mitogen-activated protein kinase and p70S6 kinase are involved. Moreover, intracellular ATP was increased in Trx1-overexpressing cells but reduced in cells overexpressing Trx2 or TrxR2, providing thus an understanding of how protein synthesis is regulated by thioredoxins.

Place, publisher, year, edition, pages
Elsevier, 2008
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-98716 (URN)10.1016/j.freeradbiomed.2007.09.012 (DOI)000251931400010 ()18045551 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
Cunnea, P., Fernandes, A., Capitanio, A., Eken, S., Spyrou, G. & Björnstedt, M. (2007). Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma. International journal of immunopathology and pharmacology, 20(1), 17-24
Open this publication in new window or tab >>Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma
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2007 (English)In: International journal of immunopathology and pharmacology, ISSN 0394-6320, Vol. 20, no 1, p. 17-24Article in journal (Refereed) Published
Abstract [en]

Hepatocellular Carcinoma (HCC) is one of the most frequent cancers worldwide, however, prognosis remains poor following its discovery. We investigate the Thioredoxin superfamily of proteins as diagnostic markers for HCC. Furthermore, we delineate possible roles of the endoplasmic reticulum member of the superfamily, ERdj5, in carcinogenesis. Using antibodies against Thioredoxin 1, Thioredoxin Reductase 1 and ERdj5, we performed immunohistochemistry on paraffin embedded liver biopsy sections from HCC patients. All three redox proteins exhibited elevated expression levels in tumor tissue compared to internal control, with ERdj5 showing a remarkable 3-fold increase. In vitro cell viability experiments using Hepatocellular Carcinoma HuH7 cells treated with ERdj5 small interfering RNA showed that ERdj5 knockdown cells exhibited less resistance to Doxorubicin (chemotherapy drug), but more resistance to Tunicamycin (Endoplasmic Stress inducer), compared to control cells. In conclusion, we introduce members of the Thioredoxin superfamily as possible immunohistochemical markers in the diagnostics of hepatocellular carcinoma and indicate a potential defensive role for ERdj5 in chemotherapeutic drug resistance.

Place, publisher, year, edition, pages
Biolife, 2007
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98711 (URN)000245120600003 ()17346424 (PubMedID)
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
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