Expression and co-cytokine function of murine thioredoxin/adult T cell leukaemia-derived factor (ADF)

Blum, Horst; Röllinghoff, Martin; Gessner, André

doi:10.1006/cyto.1996.0002

Cited by 27 publications

(25 citation statements)

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“…Thioredoxin reductase is an essential enzyme important in maintaining cellular thiol-redox homeostasis and defense against oxidant stress and also mediates important cocytokine activities via its substrate thioredoxin, which can act as a potent T-cell growth factor (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Increases in thioredoxin reductase may thus not only signal HDI-induced thiolredox imbalance but also provide an "antigenreceptor-independent" mechanism by which epithelial cell responses to exposure may promote immunologic sensitization to HDI via either a) epithelial cell-derived cytokines/ chemokines under redox-dependent transcriptional regulation (13,14) or b) immunologically active thioredoxin (21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…Increases in thioredoxin reductase may thus not only signal HDI-induced thiolredox imbalance but also provide an "antigenreceptor-independent" mechanism by which epithelial cell responses to exposure may promote immunologic sensitization to HDI via either a) epithelial cell-derived cytokines/ chemokines under redox-dependent transcriptional regulation (13,14) or b) immunologically active thioredoxin (21)(22)(23)(24)(25). Interestingly, thioredoxin reductase contains selenium, which is thought to be crucial to its role as a cellular sensor of redox potential and which, based on its biochemical properties, should be highly susceptible to nucleophilic addition reactions with diisocyanates (10,28,31).…”

Section: Discussionmentioning

confidence: 99%

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Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies.

Wisnewski

Liu

Miller

et al. 2002

Environ Health Perspect

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In this study we developed an in vitro exposure model to investigate the effects of hexamethylene diisocyanate (HDI) on human airway epithelial cells at the cellular and molecular level. We used immunofluorescence analysis (IFA) to visualize the binding and uptake of HDI by airway epithelial cell lines (A549 and NCI-NCI-H292) and microarray technology to identify HDI sensitive genes. By IFA, we observed that subcytotoxic concentrations of HDI form microscopic micelles that appear to be taken up by cells over a 3-hr period postexposure. Microarray analysis (4.6K genes) of parallel cultures identified four genes (thioredoxin reductase, dihydrodiol dehydrogenase, TG interacting factor, and stanniocalcin) whose mRNA levels were up-regulated after HDI exposure. Northern analysis was used to confirm that HDI increased message levels of these four genes and to further explore the dose dependence and kinetics of the response. The finding that HDI exposure increases thioredoxin reductase expression supports previous studies suggesting that HDI alters thiol-redox homeostasis, an important sensor of cellular stress. Another of the HDI-increased genes, a dihydrodiol dehydrogenase, encodes a protein previously shown to be specifically susceptible to HDI conjugation, and known to detoxify other hydrocarbons. Together, the data describe a novel approach for investigating the effects of HDI binding and uptake by human airway epithelial cells and begin to identify genes that may be involved in the acute response to exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies.

Wisnewski

Liu

Miller

et al. 2002

Environ Health Perspect

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“…Despite the lack of detailed information on the molecular basis of the conformational mimics generated by chemical modification or surface immobilization of the A␤ peptide, it is clear that some kind of structural constraining is involved. We thus reasoned that a similar conformational effect, besides an enhanced peptide stabilization and immunogenicity (37,38), might be obtained with the use of a scaffold protein, such as thioredoxin, with the ability to constrain the structure of short peptides inserted within its surface-exposed active site loop (38 -40) and to stimulate T-cell proliferation (41,42). This kind of recombinant antigen would be highly desirable because of its expected safety, ease of construction, and large scale production in a chemically homogeneous form.…”

Section: As a Promising New Tool For Ad Immunotherapymentioning

confidence: 99%

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Moretto

Bolchi

Rivetti

et al. 2007

Journal of Biological Chemistry

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Immunotherapy against the amyloid-␤ (A␤) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of A␤, and yet be capable of eliciting antibodies that recognize A␤ fibrils and neurotoxic A␤ oligomers but not the physiological monomeric species of A␤. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide A␤1-15 (A␤15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(A␤15) n polypeptides bearing one, four, or eight copies of A␤15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(A␤15) 4 antibody, in particular, recognized A␤42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to A␤. We have also demonstrated that anti-Trx(A␤15) 4 , which binds to human AD plaques, markedly reduces A␤ pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained A␤ fragment repeat and identify Trx(A␤15) 4 as a promising new tool for AD immunotherapy.Antipeptide antibodies are valuable tools for probing structure-function relationships in proteins as well as for therapeutic and diagnostic applications. When immunotherapy is the ultimate goal, the sequence span of the peptide, and thus the nature of the epitope(s) associated with it, as well as the conformational selectivity of the resulting antibodies may also be dictated by safety reasons. This is the case of the amyloid-␤ (A␤) 2 peptide, a major neuropathological hallmark (1-3) and a promising immunotherapeutic target of Alzheimer disease (AD) (4 -7). Following the encouraging results obtained with A␤42 vaccination in transgenic mouse models of AD (8 -10), a Phase II clinical trial utilizing preaggregated A␤42 as an antigen and the QS-21 saponin as an immunoadjuvant (AN-1792 vaccine) was halted due to the occurrence of meningoencephalitis in ϳ6% of treated patients (11-13). T-cell-mediated autoimmunity produced by the C-terminal portion of A␤ (14) along with a predominantly pro-inflammatory (T helper 1) immunoresponse and cross-reactivity with the presumably physiological monomeric forms of A␤ (A␤38 -43 peptides plus the amyloid-␤ precursor protein have been hypothesized as the main causes of these adverse effects (15-17). Of further concern is the fact that not only plaques but also soluble A␤ oligomers should be bound by a therapeutically effective antibody (18 -20). The latter represent an intermediate conformation prior to fibril formation and are presently considered as the most proximate causative agents of . S...

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“…Extracellular TRX binds to the cell membrane without a high-affinity [25,32]. Because the gut is the largest immunologic organ of the body and harbors the largest T cell compartment (lamina propria), one could assume that TRX is involved in intestinal immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…TRX stimulates cell growth [20] and is known as an autocrine growth factor for human T lymphotropic virus-1 and EBV-transformed lymphocytes [9]. TRX mediates anti-apoptotic effects [21][22][23], is a strong chemoattractant for neutrophils, monocytes, and T cells [24], and acts like a co-cytokine through stimulation of DNA synthesis in concert with IL-1 [9], IL-2 [4, 9], IL-4 [25], and IL-6 [26]. TRX was suggested to enhance proliferation by increasing the cellular uptake of cystine into PBMC [27] and by sensitizing cells for growth factors [28].…”

Section: Introductionmentioning

confidence: 99%

Potential role of thioredoxin in immune responses in intestinal lamina propria T lymphocytes

et al. 2005

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Thioredoxin (TRX) is a ubiquitous oxidoreductase with strong co-cytokine, chemoattractant and anti-apoptotic activities. TRX expression was found to be particularly elevated in the intestinal mucosa, where its physiologic function is entirely unknown. Here, we demonstrate a high level of TRX expression in lamina propria T cells (LP-T) as opposed to autologous peripheral blood T lymphocytes (PB-T). Addition of recombinant human TRX (rhTRX) to PB-T enhances TRX gene expression. This autoregulation involves the calcineurin signaling pathway, as rhTRX antagonizes the cyclosporine A (CsA)-and tacrolimus-mediated suppression of TRX gene expression. Similarly, rhTRX reverses the suppression of IL-2 mRNA production by CsA and enhances cytokine production preferentially in prestimulated cells. The differential TRX expression in LP-T versus PB-T may thus contribute to the high-level, CsA-resistant IL-2 production characteristic for CD2-stimulated LP-T. Inversely, inactivation of TRX in LP-T through inhibition of TRX reductase abolishes cytokine gene expression. TRX may play a key role in the specialized intestinal microenvironment in amplifying immediate immune responses of LP-T whenever appropriate costimulation of LP-T is provided. IntroductionThioredoxin (TRX) is a ubiquitous 12-kDa oxidoreductase containing two redox-active cysteine residues in its conserved active-center motif -Cys-Gly-Pro-Cys- [1,2]. Together with the selenoprotein TRX reductase and NADPH, it operates as a protein disulfide-reducing system [3][4][5][6][7][8]. Human PBMC express only minute amounts of TRX, which increase after mitogenic stimulation in vitro [3,9,10]. Oxidative stress through, e.g., hydrogen peroxide or after ischemia-reperfusion enhances the expression of TRX [11,12], which serves as an antioxidant in addition to intracellular glutathione [13][14][15]. Moreover, TRX is involved in the redox control of DNA binding of transcription factors like NF-jB [16,17] and AP-1 [18,19]. TRX stimulates cell growth [20] and is known as an autocrine growth factor for human T lymphotropic virus-1 and EBV-transformed lymphocytes [9]. TRX mediates anti-apoptotic effects [21][22][23], is a strong chemoattractant for neutrophils, monocytes, and T cells [24], and acts like a co-cytokine through stimulation of DNA synthesis in concert with IL-1 [9], IL-2 [4, 9], , and . TRX was suggested to enhance proliferation by increasing the cellular uptake of cystine into PBMC [27] and by sensitizing cells for growth factors [28].Upon stimulation, lymphocytes secrete TRX through a leaderless secretory pathway [29,30]. Extracellular TRX binds to the cell membrane without a high-affinity [25,32]. Because the gut is the largest immunologic organ of the body and harbors the largest T cell compartment (lamina propria), one could assume that TRX is involved in intestinal immune responses.The proliferative activity of lamina propria T lymphocytes (LP-T) towards TCR/CD3-dependent stimuli is extremely low in the normal gut, which may in part be explained by the inability of ...

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Expression and co-cytokine function of murine thioredoxin/adult T cell leukaemia-derived factor (ADF)

Cited by 27 publications

References 0 publications

Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies.

Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies.

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Potential role of thioredoxin in immune responses in intestinal lamina propria T lymphocytes

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