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IMMUNOBIOLOGY
Human thioredoxin (Trx) is the major 12-kd cellular
disulfide-reductase that on secretion acts as a cocytokine with several interleukins. Truncated Trx with the 80 N-terminal residues (Trx80), also present in plasma, was by itself a mitogenic cytokine for human
peripheral blood mononuclear cells (PBMC). This study investigated which cells in PBMC are targets of recombinant Trx80. Purified human
CD14+ monocytes, but not B or T cells, in a synthetic
medium were activated to differentiation by Trx80 as measured by
flow cytometry of surface antigens because exposure to 100 nM Trx80
increased expression of CD14, CD40, CD54, and CD86. Proliferation of
the monocytes was increased in a dose-dependent manner by Trx80 in
concentrations ranging from 10 nM to 1 µM. Trx or interleukin (IL) 2 did not induce proliferation or expression of surface antigens on
monocytes. Trx80 alone induced secretion of IL-12 from
CD40+ monocytes in the PBMC cultures and this effect was
enhanced by IL-2. Trx80 and IL-2 together were strongly synergistic to
induce secretion of interferon- Thioredoxin (Trx) is a ubiquitous 12-kd redox
enzyme that catalyzes thiol-disulfide exchange reactions via 2 cysteine
residues in the conserved active site sequence
-C-G-P-C-1-3 (single-letter amino acid codes). The
3-dimensional structure of thioredoxins (the thioredoxin fold) is
characterized by a central 5-stranded sheet surrounded by 4 alpha
helices.1-6 The active site disulfide in the oxidized Trx
is reduced to a dithiol by NADPH and thioredoxin reductase
(TrxR).1,2,7,8 Human T-cell leukemia virus I
(HTLV-I)-transformed human T cells produce a factor previously named
ADF, which is identical to human Trx.9 Trx is also
secreted from several other cell types including activated normal B
lymphocytes, B lymphocytes from B-type chronic lymphocytic leukemia,
liver cells, fibroblasts, and T lymphocytes.10,11 Among
its regulatory functions, Trx is involved in redox control of DNA
binding of transcription factors like nuclear factor- Apart from full-length Trx, a fragment of Trx, containing the 80 to 84 first N-terminal amino acids, is known. This truncated protein, Trx80,
is secreted from various cells, namely, U937 monocytes, cytotrophoblasts, CD4+ T cells,17,22-24 and is
present on the cell surface of the monocytic cell lines U937 and
THP-1.25 Trx80 is present in normal human plasma26 and we recently discovered that recombinant Trx80
alone stimulates proliferation of PBMC in a synthetic
medium.26 Truncated Trx is elevated in plasma from
patients with schistosomiasis and enhances eosinophilic cytotoxicity in
vitro.27-30 Trx80 is a dimer in solution and is devoid of
catalytic oxidoreductase activity, but Trx can reduce disulfides in
Trx80.26 It has also been reported that Trx80 as a fusion
protein increased human immunodeficiency virus (HIV) viral replication
in infected macrophages, whereas Trx decreased the same.31
Interleukin 12 is a disulfide-linked cytokine composed of a 35-kd light
chain (p35) and a 40-kd heavy chain (p40).32,33 It was
first purified from conditioned media of an Epstein-Barr virus
(EBV)-transformed human B cell line.34-36 However, the
major producers of IL-12 in PBMC are monocytes or monocytic-derived macrophages, although B cells may also produce IL-12.37
There are few known endogenous inducers of IL-12. Bacteria, bacterial products, and intracellular parasites are strong inducers of IL-12 expression37; however, the initial events that induce the
production of IL-12 are not known. IL-12 stimulates proliferation of
hematopoietic progenitor cells in response to other growth factors,
such as IL-3 and IL-11.38 Moreover, it induces
proliferation of preactivated T cells and natural killer (NK) cells,
and the induction of proliferation of T cells is IL-2
independent.39 IL-12 also stimulates production of Th1
cytokines such as interferon- To understand which cells in human PBMC are stimulated by Trx80, we
have purified human monocytes and T and B cells from healthy blood
donors. We found that Trx80 activates monocytes to proliferate and
express elevated levels of CD14, CD40, CD54, and CD86. We also observed
that Trx80 by itself induces a Th1 response in PBMC by inducing
secretion of IL-12 and IFN- Materials
Purification of CD14+, CD14 Cell proliferation assay of purified CD14+,
CD14 Flow cytometry analysis of surface markers The CD14+, CD14 , or CD3+
cells were grown in AIM V medium supplemented with 2 mM
L-glutamine, 100 U/mL penicillin, and 100 U/mL streptomycin
for 3 days at the same conditions as described above in ultralow
attachment wells pretreated with AIM V medium according to
manufacturer's instruction. Cells were stimulated with either Trx80 or
Trx at 100 nM or 1 µM, IL-2 at 20 U/mL, and with IL-2 at 20 U/mL with
either 100 nM or 1 µM Trx or Trx80. Cells were harvested by adding
cold PBS to cell cultures, incubated on ice for 10 minutes, and
resuspended with a Pasteur pipette. Cells were then incubated for 45 minutes on ice with FITC-conjugated CD14, CD40, and CD86 antibodies and
isotype-matched control antibodies and PE-conjugated CD3 and CD54
antibodies and isotype-matched control antibodies, washed once with 1 mL PBS and finally resuspended in 500 µL PBS. The cells were analyzed
in a FACSCalibur flow cytometer (Becton Dickinson) using Cell Quest
software (Becton Dickinson). In each sample 5000 cells were analyzed.
Dead cells were excluded by cell size or by staining with
propidium iodide.
Detection of cytokines secreted to cell medium The PBMC, CD14+, CD14, or
CD3+ cells, respectively, were cultured in 24-well
flat-bottomed wells for 24, 48, or 72 hours under the same conditions
described above. Cells were stimulated with 10 nM to 1 µM Trx80 or
Trx with or without 20 U/mL IL-2, with IL-2 at 20 U/mL alone, with 10 ng/mL LPS and with 1 µg/mL PMB. At defined times, cells were
harvested and centrifuged and supernatants were collected in 2 Eppendorf tubes, which were frozen at  20°C and analyzed in
duplicate wells using sandwich ELISA for IL-4, IL-5, IL-12, or IFN-
according to the manufacturer's instructions. The sandwich ELISA for
IL-12 detected both IL-12 heavy chain (p40) and the heterodimer (p75).
The detection limit of the IL-12 ELISA was 0.3 ng/mL and for the IL-4,
IL-5, and IFN- ELISA the detection limits were 0.03 ng/mL.
Detection of intracellular cytokines The PBMC were cultured in 6-well ultralow attachment wells for 24, 48 or 72 hours as above. At a time point 22 hours before terminating cultures, Brefaldin A was added, to inhibit export via the Golgi pathway, to a final concentration of 0.1 ng/mL cell culture. Cells were then harvested, fixed with 4% paraformaldehyde for 45 minutes on ice, washed twice with PBS, and permeabilized with washing buffer (Pharmingen) containing saponin. Subsequently, PBMC were incubated for 45 minutes on ice with APC-conjugated anti-IL-12 antibody and isotype-matched control antibody and FITC-conjugated CD14, CD40, and CD19 antibodies and isotype-matched control antibodies. The APC-conjugated anti-IL-12 antibody detected both IL-12 heavy chain (p40) and IL-12 heterodimer. Cells were then washed twice with washing buffer containing saponin and resuspended in 500 µL PBS. The cells were analyzed in a FACSCalibur. In each sample 5000 cells from the large cell population, that is, monocytes, and 5000 cells from the small cell population, that is, B and T cells, were analyzed.Statistics Thymidine incorporation and flow cytometry data of the CD14+ monocytes were compared using the nonparametric Wilcoxon matched pairs test. A P value of less than .05 was considered statistically significant.
Trx80 induces proliferation of monocytes Purified CD14+ monocytes were incubated in the synthetic AIM V medium and exposed to Trx80 for 3 days with 3H-thymidine added during the last 12 hours of incubation. Trx80 stimulated DNA synthesis in a dose-dependent manner, whereas Trx or IL-2 alone (Figure 1A) or added together (data not shown) gave no increase in thymidine incorporation. With 1 µM Trx80, a 35-fold increase of thymidine incorporation was observed compared to unstimulated monocytes (n = 7, P < .05). Trx80 at 10 nM gave no increase in thymidine incorporation, whereas Trx80 at 100 nM gave a 4-fold increase (n = 7, P = .06) (Figure 1A). There were no synergistic effects between Trx80 and IL-2 or between Trx and IL-2 on cell proliferation (data not shown). When a mixture of B and T cells or when pure T cells were treated with Trx80, no increase in cell proliferation was seen (data not shown). The background levels of 3H-thymidine incorporation differed from donor to donor, although all cultures had more than 94% CD14+ cells. The response to Trx80 also varied among the different donors. However, in 7 of 7 donors Trx80 gave an increase in 3H-thymidine incorporation in the purified monocytes, and this increase differed from 7- to 80-fold among the donors when 1 µM Trx80 was used. In 5 of the 7 donors this increase was more than 19-fold when the monocytes were stimulated with 1 µM Trx80 (Figure 1A). The viability of the purified monocytes after 3 days in culture also varied among the different donors. However, Trx and Trx80 increased the viability of the cultured monocytes from all 7 donors (data not shown).
To further ascertain that the effects seen were truly generated by Trx80, control experiments with PMB and LPS were performed. Addition of 10 ng/mL LPS slightly induced proliferation of monocytes. This effect was totally abolished when 10 ng/mL LPS and 1 µg/mL endotoxin inhibitor PMB were added together (Figure 1B). When PMB was added to cultured monocytes stimulated with Trx80 no difference in proliferation was seen compared to when only Trx80 was added (Figure 1B). Trx80 enhances the expression of CD14, CD40, CD54, and CD86 in monocytes The CD14+ monocytes isolated from PBMC up-regulated the expression of several surface antigens after stimulation with Trx80 for 3 days; however, this was not the case when CD14+ monocytes were treated with Trx and IL-2 alone or in synergy (Figure 2). When a mixture of T and B cells or purified T cells were stimulated with 100 nM or 1 µM Trx80, no increase in expression of surface antigens was seen (data not shown).
The surface expression of the monocyte marker CD14 increased significantly in a dose-dependent fashion when cells were stimulated with Trx80. At the starting point of each experiment there were more than 94% CD14+ cells. Trx80 at 100 nM gave a 2-fold increase of the mean fluorescence index (MFI) of CD14, whereas 1 µM Trx80 gave a 4- to 5-fold increase in MFI compared to unstimulated cells (P < .05, n = 5; Figure 2A). When monocytes were treated with Trx or IL-2, no change in MFI for CD14 was seen (Figure 2A). No synergy with Trx or Trx80 together with IL-2 was seen when CD14 expression was analyzed (data not shown). The expression of the activation marker CD40, the adhesion molecule CD54, and the costimulatory CD86 was increased significantly by Trx80 compared to unstimulated cells (P < .05, n = 5). When the experiment started there were between 40% and 90% CD40+ cells in the different subjects, apart from one donor who had only 7% CD40+ cells. No increased expression was seen with IL-2 or Trx; however, 100 nM or 1 µM Trx80 increased the MFI of CD40 expression by 2- to 3-fold compared to unstimulated cells (Figure 2B). No synergistic effects on CD40 expression with IL-2 and Trx or Trx80 was seen (data not shown). More than 88% of the CD14+ monocytes in all 5 subjects tested expressed CD54. The proportion of CD86+ monocytes was between 30% to 95% in the different subjects. No change in the proportion of CD54+ and CD86+ cells was seen during the culture time. However, the MFI of CD54 and CD86 increased 2- to 3-fold compared to unstimulated cells when cells were stimulated with 100 nM and 1 µM Trx80 (P < .05, n = 5) (Figure 2C,D). No synergy was seen with IL-2 and Trx80 (data not shown). Trx80 induces secretion of IL-12 and IFN- and the Th2 cytokines
IL-4 and IL-5. No Th2 cytokines were detected when PBMC, CD14+, CD14 or T cells were stimulated with
Trx80, Trx, or IL-2 either alone or in synergy for 24 to 72 hours in
culture (data not shown). In PBMC cultured for 3 days with no stimulus,
IL-12 was undetectable in the cell culture medium. However, when PBMC
were stimulated with 100 nM Trx80, the IL-12 levels were between 0.5 and 2 ng/mL and with 1 µM Trx80 the levels were between 1 and 9 ng/mL
(n = 9). With IL-2 alone or in combination with Trx, no secretion of IL-12 was seen. However, the stimulation of IL-12 secretion caused by
Trx80 was enhanced by IL-2. Thus, PBMC stimulated with 20 U/mL IL-2 and
1 µM Trx80 together had IL-12 levels between 5 and 12 ng/mL (n = 9;
Figure 3). IL-12 levels in the cell
culture medium increased over time when PBMC were stimulated with Trx80
or Trx80 and IL-2. The highest levels of IL-12 was seen after 3 days
(Figure 4). LPS at 10 ng/mL gave
approximately double the amount of IL-12 in PBMC supernatants compared
to 1 µM Trx80 (12 ng/mL and 6 ng/mL, respectively). When 10 ng/mL LPS
and 1 µg/mL PMB were added to PBMC cultures, the effect of LPS on
secretion of IL-12 by PBMC was reduced, whereas when 1 µM Trx80 and 1 µg/mL PMB were used the effect of Trx80 was unchanged (Figure
5).
A dramatic increase in IFN-
Trx80 stimulates production of IL-12 from CD40+ monocytes in PBMC When PBMC were stimulated with 1 µM Trx80 or Trx80 in combination with 20 U/mL IL-2 for 48 hours from 5% to 6% of the CD40+ cells in the large cell population in PBMC became IL-12+ as analyzed by FACS analysis (Figure 7B,D). There were no difference in IL-12+ cells between PBMC stimulated with only Trx80 at 1 µM and PBMC stimulated with Trx80 and IL-2 (Figure 7B,D). All cells in the large population expressing IL-12 were CD40+ (Figure 7). Approximately 50% of the large cells expressing IL-12 were CD14+ (data not shown). However, Brefaldin A, which was used to inhibit the export of IL-12 via the Golgi pathway, seemed to have a negative effect on the CD14 expression in the large cell population; when PBMC were stimulated with 1 µM Trx80 for 2 days, 78% of the cells in the large cell population in PBMC were CD14+. If Brefaldin A was added 22 hours before harvesting, the CD14+ cells in the large cell population in the PBMC culture had decreased to 38% (data not shown). No cells in the small population, which consisted of CD3+ T cells and CD19+ B cells, expressed IL-12 when cultured unstimulated, with Trx80 or IL-2 alone or in combination or with LPS at 100 ng/mL (data not shown). When PBMC were cultured with 20 U/mL IL-2 there were 1.3% of the CD40+ cells in the large cell population that expressed IL-12 (Figure 7C). No unstimulated cells in the large population expressed IL-12 (Figure 7A). LPS at 100 ng/mL induced IL-12 expression in the large cells to a similar extent as Trx80 (Figure 7E).
Trx80 is an extracellular natural cleavage product of human
cytosolic thioredoxin24,30,31 lacking the c-terminal
In this study we demonstrate that the primary target cell in PBMC for
the mitogenic effects of Trx80 is the monocyte. Addition of Trx80
induced proliferation and differentiation of isolated monocytes as
measured by thymidine incorporation and enhanced expression of the
surface markers CD14, CD40, CD54, and CD86. Trx80, by itself, and in
combination with IL-2, induced secretion of the Th1 inducer IL-12 from
normal resting human PBMC. In addition, Trx80 in synergy with IL-2
induced secretion of IFN- When purified monocytes were stimulated for 3 days with Trx80, CD14 expression on the cell surface was increased 5-fold. One of the major biologic significances of the enhanced CD14 expression by Trx80 should be in the defense against intracellular and extracellular parasites by innate immunity, because CD14 is a receptor for LPS, with a broad substrate specificity.44 In addition, CD14 is also important for recognition and removal of apoptotic cells.45 Moreover, CD14 expression promotes survival of cells and antagonizes apoptosis.44 Th2 cell-derived cytokines such as IL-4 are able to induce monocyte apoptosis. This process is preceded by down-regulation of the CD14 surface receptor.44 Baldini and colleagues have shown a genetic polymorphism in the 5' flanking region of the CD14 gene, which can be one cause of the variation among different donors in CD14 expression. In their study, 50% in the population were heterozygotes and 21% were homozygotes for this mutation.46 The homozygotes had higher levels of circulating soluble CD14, which most probably arises from membrane-bound CD14.46 In addition, our results show that Trx80 induces phenotypic changes on
monocytes that will influence T-cell activation. Trx80 enhanced
expression of CD40 on monocytes 3-fold measured as MFI. Moreover, in
one donor in which only 7% of the CD14+ monocytes
expressed CD40, Trx80 turned CD40 Trx80 at concentrations between 100 nM and 1 µM induced secretion of
IL-12 in a dose-dependent fashion from human resting PBMC. Trx or IL-2
alone did not have this property. Moreover, we found that the cells in
PBMC cultures expressing IL-12 were the large CD40+
monocytes. It is clear that monocytes require, in addition to Trx80,
costimulatory signals to be able to induce IL-12 production because
purified CD14+ monocytes or CD19+ B cells did
not increase secretion of IL-12 when stimulated with Trx80. It is
probable that the required costimulatory signals are given by T cells.
In support of this Shu and coworkers found that monocytes cultured for
48 hours with GM-CSF and IFN- One of the most important properties of IL-12 is its ability to induce
the production of IFN- Full-length Trx is known to be secreted from cells and have cocytokine activities extracellularly.10,11,17 Among other functions Trx up-regulates the IL-2 receptor on T cells.16,54,55 Trx levels are increased in plasma from HIV-infected individuals and also in inflammatory diseases.56-58 The exact redox state of secreted Trx is unknown, but it should be kept oxidized by the oxidizing extracellular environment. Secretion of Trx and Trx80 occur in conditions of oxidative stress. Our results suggest a novel mechanism for extracellular Trx, namely, to act as a reservoir for Trx80, which can be generated by cleavage of full-length Trx by macrophages.31 Trx80, which is devoid of redox activity,26 could then activate monocytes, as shown herein, and eosinophilic cells.26,29,59 Our results clearly demonstrate that Trx80 is a potent inducer of a Th1 response in normal resting human PBMC and that the monocyte is the primary target cell for the molecule. Moreover, our data suggest that Trx80-activated monocytes could be more efficient in phagocytosing apoptotic cells, invasive bacteria, or parasites via the CD14 receptor. The increased CD14 expression may also confer survival advantages for monocytes.
Medical Nobel Institute for Biochemistry, Department of Biochemistry and Biophysics, Karolinska Institutet, and the Department of Medicine, Unit of Clinical Allergy Research, Karolinska Institutet and Hospital, Stockholm, Sweden.
Submitted October 30, 2000; accepted January 24, 2001.
Supported by grants from the Swedish Cancer Society (961), the Swedish Medical Research Council (grants 03X-3529, 03XS-13005, and 16X-7924), the Karolinska Institute, the Swedish Asthma and Allergy Association, the Swedish Council for Work Life Research, and the Swedish Foundation for Health Care Sciences and Allergy Research. J. A.-C. is the recipient of a fellowship from AMF-Sjukförsäkrings Jubilee Foundation for Research in National Diseases, and R. G. is the recipient of a fellowship from the Wenner-Gren Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Arne Holmgren, Medical Nobel Institute for Biochemistry, Dept of Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden; e-mail: Arne.Holmgren{at}mbb.ki.se.
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  L. Billiet, C. Furman, G. Larigauderie, C. Copin, K. Brand, J.-C. Fruchart, and M. Rouis Extracellular Human Thioredoxin-1 Inhibits Lipopolysaccharide-induced Interleukin-1{beta} Expression in Human Monocyte-derived Macrophages J. Biol. Chem., December 2, 2005; 280(48): 40310 - 40318. [Abstract] [Full Text] [PDF]
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 K. Pekkari, M. T. Goodarzi, A. Scheynius, A. Holmgren, and J. Avila-Carino Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK Blood, February 15, 2005; 105(4): 1598 - 1605. [Abstract] [Full Text] [PDF]
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A. Liu, J. L. Arbiser, A. Holmgren, G. Klein, and E. Klein PSK and Trx80 inhibit B-cell growth in EBV-infected cord blood mononuclear cells through T cells activated by the monocyte products IL-15 and IL-12 Blood, February 15, 2005; 105(4): 1606 - 1613. [Abstract] [Full Text] [PDF]
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 D. Yamazaki, K. Motohashi, T. Kasama, Y. Hara, and T. Hisabori Target Proteins of the Cytosolic Thioredoxins in Arabidopsis thaliana Plant Cell Physiol., January 15, 2004; 45(1): 18 - 27. [Abstract] [Full Text] [PDF]
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 H. Nakamura, L. A. Herzenberg, J. Bai, S. Araya, N. Kondo, Y. Nishinaka, L. A. Herzenberg, and J. Yodoi Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis PNAS, December 6, 2001; (2001) 191498798. [Abstract] [Full Text] [PDF]
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H. Nakamura, L. A. Herzenberg, J. Bai, S. Araya, N. Kondo, Y. Nishinaka, L. A. Herzenberg, and J. Yodoi Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis PNAS, December 18, 2001; 98(26): 15143 - 15148. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
B (NF-
(TNF-
