Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xu, L.-G.
Right arrow Articles by Shu, H.-B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xu, L.-G.
Right arrow Articles by Shu, H.-B.
(Journal of Leukocyte Biology. 2002;72:410-416.)
© 2002 by Society for Leukocyte Biology

Identification of downstream genes up-regulated by the tumor necrosis factor family member TALL-1

Liang-Guo Xu*, Min Wu*,{dagger}, Jiancheng Hu*, Zhonghe Zhai{dagger} and Hong-Bing Shu*,{dagger}

* Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver; and
{dagger} Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China

Correspondence: Dr. Hong-Bing Shu, Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, K516c, Denver, CO 80206. E-mail: shuh{at}njc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
TALL-1 is a member of the tumor necrosis factor family that binds to BCMA, TACI, and BAFF-R, three receptors mostly expressed by mature B lymphocytes. Previous studies have shown that the TALL-1 signaling is critically involved in B cell proliferation, maturation, and progression of lupus-like, autoimmune diseases. In this report, we performed cDNA subtractive hybridization experiments to identify downstream genes up-regulated by TALL-1. These experiments indicated that 10 genes, including interleukin (IL)-10, lymphocyte activation gene-1 (LAG-1), GCP-2, PBEF, ferritin, PIM-2, TFG, CD27 ligand, DUSP5, and archain, were up-regulated at the mRNA level by TALL-1 stimulation in B lymphoma RPMI-8226 cells and/or primary B lymphocytes. We also demonstrated that TALL-1 activated transcription of IL-10 and LAG-1 in a nuclear factor-{kappa}B-dependent manner in reporter gene assays. Moreover, our findings indicated BAFF-R, but not TACI, could dramatically up-regulate IL-10 secretion by RPMI-8226 cells. The identification of TALL-1-up-regulated genes will help explain the mechanisms of TALL-1-triggered biological and pathological effects and to identify molecular targets for intervention of lupus-like autoimmune diseases.

Key Words: B lymphocytes • autoimmunity • IL-10 • gene regulation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
TALL-1, also called BAFF, Blys, THANK, and zTNF4, is a member of the tumor necrosis factor (TNF) family of ligands recently identified by us and others [1 2 3 4 5 ]. TALL-1 is specifically and constitutively expressed by monocytes and macrophages [1 , 3 ]. Like most members of the TNF family, the extracellular domain of TALL-1 can be cleaved to form a soluble cytokine [2 ].

TALL-1 signals through three receptors, including BCMA, TACI, and BAFF-R, which are members of the TNF receptor family [5 6 7 8 9 10 11 12 13 14 15 16 ]. All three receptors are mainly expressed by mature B lymphocytes, and TACI is also induced in a subset of T cells following their activation [5 6 7 8 9 10 11 12 13 14 15 16 ]. In vitro, soluble TALL-1 (sTALL-1) can potently stimulate B lymphocyte proliferation alone or in synergy with anti-immunoglobulin (Ig)M [2 , 3 , 10 11 12 13 ]. Administration of recombinant sTALL-1 or overexpression of sTALL-1 in mice leads to increased numbers of mature B lymphocytes, splenomegaly, anti-DNA antibodies, proteinuria, and glomerulonephritis, phenotypes that mimic those of systemic lupus erythemasus (SLE) [3 , 5 , 14 , 17 , 18 ]. Conversely, it has been shown that recombinant sTACI-Ig fusion proteins could significantly inhibit progression of lupus-like autoimmune syndrome and collagen-induced arthritis in animal models [19 ]. Recently, gene knockout studies further confirmed that TALL-1 is required for normal B cell development [20 ]. Surprisingly, gene inactivation studies also indicated that BAFF-R, but not TACI and BCMA, is required for TALL-1-triggered B cell development [15 , 21 22 23 ]. Taken together, these studies suggest that the TALL-1 signaling plays critical roles in regulation of B cell function and autoimmune diseases.

Like many other members of the TNF receptor family, BCMA and TACI can bind to TNF receptor-associated factor proteins and activate the transcription factor nuclear factor (NF)-{kappa}B and the serine/threonine protein kinase c-jun NH2-terminal kinase [10 11 12 13 , 16 , 24 ]. In addition, it has been shown that TACI can activate the transcription factor NF-AT [9 ]. These studies suggest that TALL-1 signaling may lead to transcriptional induction of downstream genes.

In this paper, we report the identification of genes transcriptionally induced by TALL-1 stimulation in B cells using a cDNA subtractive hybridization approach.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Reagents and cell culture
Mammalian-derived, recombinant, Flag-tagged, human sTALL-1 [10 ] and Escherichia coli-derived, recombinant, His6-tagged, human sTALL-1 and TALL-1 mutant [25 ] were previously described. The human embryonic kidney 293 cell line (Dr. Zaodan Cao, Tularik, Inc., S. San Francisco, CA) and the I{kappa}B{alpha} (SS32/36AA) expression plasmid (Dr. David Goeddel, Tularik, Inc.) were provided by the indicated investigators. The RPMI-8226 B lymphoma cell line was purchased from American Type Culture Collection (Manassas, VA).

RPMI-8226 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS). Cells (293) were maintained in high glucose Dulbecco’s modified Eagle’s medium containing 10% fetal calf serum.

Flow cytometry analysis
RPMI-8226 cells (~1x106) were incubated in staining buffer (phosphate-buffered saline/2% FBS) in the absence or presence of Flag-sTALL-1 (100 ng/ml) for 40 min. Cell staining was performed by sequential incubation (each 40 min) with anti-Flag monoclonal antibody (mAb; 1 µg/ml) and RPE-conjugated goat anti-mouse IgG (1:200 dilution) in staining buffer. Cells were washed two times with staining buffer following each incubation. The fluorescence exhibited by the stained cells was measured using a FACScan flow cytometer (Becton Dickson, San Jose, CA).

Electrophoretic mobility shift assays
RPMI-8226 cells (~2x106) were treated with His6-sTALL1 (200 ng/ml) and TNF (20 ng/ml) or were left untreated for 30 min, and then nuclear extracts were prepared. Aliquots of the nuclear extracts (20 µg) were incubated with 0.4 ng radiolabeled, double-stranded oligonucleotide containing the following NF-{kappa}B-binding sequence: 5' GGGGACTTTCCC 3'. Each reaction was supplemented with 0.8 µg poly(dIdC) for blocking nonspecific binding. Nucleoprotein complexes were resolved by electrophoresis on a 6% nondenaturing acrylamide gel in Tris-borate-ethylenediaminetetraacetate buffer.

B lymphocyte isolation
Dr. Peter Henson (National Jewish Medical and Research Center, Denver, CO) provided lymphocytes from peripheral blood of healthy donors were provided. Primary B lymphocytes were purified using anti-CD19 Dynal beads and DETACHaBead anti-CD19 (Dynal, Great Neck, NY) by following procedures suggested by the manufacturer.

RNA isolation
RPMI-8226 cells (~1x108) were treated with His-sTALL-1 (200 ng/ml) or left untreated for 4 h. mRNAs were then isolated with the Message Marker mRNA isolation system (Life Technologies, Gaithersburg, MD) following procedures recommended by the manufacturer.

Reverse transcriptase-polymerase chain reaction (RT-PCR)
RT-PCR was performed as previously described [1 ].

cDNA subtractive hybridization screening
cDNA subtractions were performed with the PCR-Select cDNA subtraction kit (Clontech, Palo Alto, CA) following procedures recommended by the manufacturer.

Northern blot hybridization
mRNAs from TALL-1-treated and untreated cells were fractionated in 1.2% agarose gels and transferred to pure nitrocellulose membranes. Hybridization was performed with the Rapid Hybridization Buffer (Clontech) at 65°C for 2 h. Blots were washed under high stringent conditions.

Construction of reporter plasmids
To construct the interleukin (IL)-10-luciferase reporter vector, an ~1.5-kb fragment of the human IL-10 promoter was amplified from human leukocyte genomic DNA with the following two primers: 5' primer-5'-AAACCCGGGTCAGTGTTCCTCCCAGTTACAGTCTAAACTG-3' and 3' primer-5'-TCTCGGAGATCTCGAAGCATGTTAGGCAGGTTG-3'. The amplified fragment was digested with XmaI/BglII restriction enzymes and inserted into the XmaI/BglII sites of the pGL3-basic plasmid (Promega, Madison, WI).

To construct the lymphocyte activation gene-1 (LAG-1)-luciferase reporter vector, an ~2.6-kb fragment of human LAG-1 promoter was amplified from human leukocyte genomic DNA with the following two primers: 5' primer-5'-AAGGTACCCAATAATGGGATTGCTGGGTTGAATGGTAATTC-3' and 3' primer-5'-AACCCGGGAGTTCCTCTCAGCTTCTCTTCCCCAGGGCG-3'. The amplified fragment was digested with KpnI/XmaI restriction enzymes and inserted into the KpnI/XmaI sites of the pGL3-basic plasmid (Promega).

Reporter gene assays
Cells (293; ~2x105) were seeded on six-well (35-mm) dishes and were transfected the following day with 0.5 µg IL-10 or LAG-1 luciferase reporter constructs and the indicated expression plasmids. Within the same experiment, each transfection was performed in triplicate, and where necessary, enough amount of empty control plasmid was added to keep each transfection receiving the same amount of total DNA. To normalize for transfection efficiency and protein amount, 0.5 µg respiratory syncytial virus-ß-gal plasmid was added to all transfections. Fourteen hours after transfection, cells were treated with His-sTALL-1 (200 ng/ml) or were left untreated for 6 h. Luciferase reporter assays were performed using a luciferase assay kit (Pharmingen, San Diego, CA) and following the manufacturer’s protocols. ß-Galactosidase activity was measured using the Galacto-Light chemiluminescent kit (TROPIX Inc., Bedford, MA). Luciferase activities were normalized on the basis of ß-galactosidase expression levels.

Establishing RPMI-8226 stable cell lines
cDNAs encoding for human BCMA, TACI, and BAFF-R were amplified from a B cell cDNA library by PCR and inserted into a C-terminal, HA-tagged pcDNA3 plasmid [10 ]. The plasmids were linearized and transfected into RPMI-8226 cells by electroporetation. The transfected cells were selected by G418 (1 mg/ml) for 2 weeks. Cells with high-receptor expression in the stable cell lines were further sorted with Flag-tagged sTALL-1 by flow cytometry. Overexpression of the receptors was confirmed by Western blot with anti-HA antibody.

Enyzme-linked immunosorbent assays (ELISAs)
Human IL-10 ELISAs were performed using the human IL-10 ELISA Ready-Set-Go kit (eBioscience, San Diego, CA) by following procedures recommended by the manufacturer.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
To identify genes regulated by TALL-1, it is ideal to use primary B lymphocytes. However, as it is difficult to obtain a large quantity of primary B lymphocytes, we have selected a B lymphoma cell line RPMI-8226 for our experiments. Flow cytometry analysis indicated that TALL-1 could bind to the plasma membrane of RPMI-8226 cells (Fig. 1A ). RT-PCR experiments demonstrated that all three TALL-1 receptors, including BCMA, TACI, and BAFF-R, are expressed by RPMI-8226 cells (Fig. 1B) . In addition, TALL-1 could activate the transcription factor NF-{kappa}B in these cells, as suggested by gel-shift experiments (Fig. 1C) . These results suggest that TALL-1 can signal in RPMI-8226 cells.



View larger version (33K):
[in this window]
[in a new window]
  		Figure 1. RPMI-8226 cells are responsive to TALL-1. (A) TALL-1 binds to the plasma membrane of RPMI-8226 cells. RPMI-8226 cells were incubated with control buffer (open histogram) or Flag-sTALL-1 (100 ng/ml; shaded histogram). Cells were washed and analyzed by flow cytometry with an anti-Flag mAb. (B) Expression of TALL-1 receptors in RPMI-8226 cells. Total RNA was isolated from RPMI-8226 cells, and RT-PCR was performed with primers corresponding to the coding sequences of the indicated receptors. *, Expected bands. (C) Activation of NF-{kappa}B by TALL-1 in RPMI-8226 cells. RPMI-8226 cells were treated with control buffer (lane 1), sTALL-1 (200 ng/ml; lane 2), or TNF (20 ng/ml; lane 3) for 30 min, and NF-{kappa}B activation was examined by gel-shift assays. The specificity of NF-{kappa}B bands was confirmed by complete competition with unlabeled {kappa}B probe (lane 4).

 
To identify genes regulated by TALL-1, we isolated mRNAs from TALL-1- or control-treated RPMI-8226 cells and performed two parallel cDNA subtraction experiments. Briefly, to identify genes up-regulated by TALL-1, we performed "forward" subtraction in which the cDNAs from TALL-1-treated cells were used as "tester", and the cDNAs from control-treated cells were used as "driver". To identify genes down-regulated by TALL-1, we performed "reverse" subtraction in which the cDNAs from control-treated cells were used as "tester," and the cDNAs from TALL-1-treated cells were used as "driver." The subtracted cDNA samples were cloned into the pGEM vector, and the cDNA inserts were sequenced.

We sequenced a total of 50 clones derived from the forward subtraction. Blast searches indicate that these clones represent 44 different genes. To confirm whether expression levels of these genes are truly regulated by TALL-1, we performed Northern blot hybridization experiments for all the 44 potential, TALL-1, up-regulated genes. These experiments indicated that the mRNA levels of 10 of the identified genes, including IL-10, LAG-1, granulocyte chemotactic protein-2 (GCP-2), pre-B cell colony-enhancing factor (PBEF), CD27 ligand, PIM-2, ferritin, archain, TRK-fused gene (TFG), and DUSP5 (see below for description of these genes), were significantly up-regulated by TALL-1 stimulation (Fig. 2 ). The mRNA levels of the other clones are not significantly changed by TALL-1 stimulation (data not shown), suggesting these genes are false positives of the cDNA subtraction experiments.



View larger version (64K):
[in this window]
[in a new window]
  		Figure 2. Northern blot analysis of gene expression up-regulated by TALL-1 in RPMI-8226 B lymphoma cells. RPMI-8226 cells were treated with sTALL-1 (200 ng/ml; +) or were left untreated (-) for 4 h, and total RNAs were isolated for Northern blot analysis with the indicated probes.

 
To confirm whether TALL-1 can up-regulate expression of the identified genes in primary B lymphocytes, we performed RT-PCR analysis for 7 of the 10 identified genes. These experiments indicated that wild-type sTALL-1, but not an inactive sTALL-1 mutant [25 ], could dramatically up-regulate mRNA expression of IL-10, LAG-1, PBEF, and PIM2 (Fig. 3 ). In the same experiments, sTALL-1 only slightly up-regulated mRNA expression of CD27L, ferritin, and archain (Fig. 3) . These data suggest that TALL-1 can significantly up-regulate mRNA expression of IL-10, LAG-1, PBEF, and PIM2 in primary B lymphocytes.



View larger version (48K):
[in this window]
[in a new window]
  		Figure 3. RT-PCR analysis of gene expression up-regulated by TALL-1 in primary B lymphocytes. Primary B lymphocytes were treated with sTALL-1 (200 ng/ml) or sTALL-1 mutant (200 ng/ml), or were left untreated (-) for 4 h, and RT-PCR was performed with primers corresponding to the indicated genes.

 
We analyzed five clones from the reverse subtraction. Northern blot experiments indicated that one of the five clones, which encodes for elongation factor 1{alpha}, had a lower mRNA level in TALL-1-treated cells than in untreated cells (Fig. 4 ). mRNA levels of the other four clones had no significant difference in TALL-1-treated and untreated cells (data not shown). These clones also represent artificial clones from the subtraction.



View larger version (38K):
[in this window]
[in a new window]
  		Figure 4. Northern blot analysis of expression level of elongation factor 1{alpha} down-regulated by TALL-1. RPMI-8226 cells were treated with sTALL-1 (200 ng/ml; +) or were left untreated (-) for 4 h, and total RNAs were isolated for Northern blot analysis.

 
To determine whether TALL-1 transcriptionally regulates the identified genes, we determined whether TALL-1 could activate the promoters of these genes. We selected IL-10 and LAG-1 for this analysis because they are dramatically up-regulated by TALL-1 in B lymphoma and primary B lymphocytes, and their promoters were well-defined. To do this, we isolated the promoters of IL-10 and LAG-1 genes and subcloned them into a luciferase reporter construct. Previously, it has been shown that overexpression of TALL-1 receptor BCMA can activate NF-{kappa}B in 293 cells, and TALL-1 can further potentiate BCMA-mediated NF-{kappa}B activation [10 ]. We examined whether overexpression of BCMA could activate the IL-10 and LAG-1 promoters by reporter gene assays. As shown in Figure 5 , overexpression of BCMA activated IL-10 and LAG-1 promoters. In addition, TALL-1 further potentiated BCMA-mediated activation of the LAG-1 promoter. TALL-1 did not potentiate BCMA-mediated activation of IL-10 promoter, probably because of saturation of IL-10 activation by overexpression of BCMA. Moreover, I{kappa}B{alpha} (SS/AA), an I{kappa}B{alpha} mutant that has been shown to inhibit NF-{kappa}B activation, completely inhibited TALL-1/BCMA-triggered activation of the IL-10 and LAG-1 promoters. Taken together, these data suggest that the TALL-1/BCMA ligand/receptor pair activates transcription of IL-10 and LAG-1 in a NF-{kappa}B-dependent manner.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 5. Activation of LAG-1 and IL-10 promoters by TALL-1/BCMA. Cells (293; ~2x105) were transfected with 0.5 µg LAG-1-luciferase (A) or IL-10-luciferase (B) reporter vectors, together with 1 µg each of the indicated mammalian expression plasmids. Fourteen hours after transfection, cells were treated with sTALL-1 (solid bars) or were left untreated (open bars) for 6 h, and luciferase assays were performed. Data shown are averages and standard deviations of relative luciferase activities from one representative experiment in which each transfection has been performed in triplicate.

 
We also determined whether TALL-1 up-regulates IL-10 production at protein level and the relative contribution of the three TALL-1 receptors in this action. To do this, we attempted to make stable RPMI-8226 cell lines overexpressing BCMA, TACI, and BAFF-R, respectively. In these experiments, our extensive effort failed to obtain a stable, BCMA-overexpressing cell line, suggesting the possibility that overexpression of BCMA is lethal in RPMI-8226 cells. In the same experiments, we easily obtained RPMI-8226 cell lines stably overexpressing TACI and BAFF-R (Fig. 6 ). We then determined secreted IL-10 protein levels in the cell culture supernatants of these stable cell lines by ELISA. We found that the IL-10 protein level secreted by the BAFF-R-overexpressing cell line was approximately seven times higher than that secreted by the empty control vector-transfected cell line (Fig. 6) . In contrast, the IL-10 level secreted by TACI overexpressing the stable cell line was similar to that secreted by the control cell line (Fig. 6) . These data suggest that signaling by BAFF-R, but not TACI, can dramatically up-regulate IL-10 protein in RPMI-8226 B lymphoma cells.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 6. IL-10 protein is up-regulated by BAFF-R. Cell culture supernatants from RPMI-8226 stable cell lines overexpressing TACI, BAFF-R, or a control stable line were examined for IL-10 secretion by ELISA (upper panel). Overexpression of C-terminal, HA-tagged TACI and BAFF-R in the stable cell lines was confirmed by Western blot with anti-HA antibody (lower panel).

 
Among the TALL-1-regulated genes identified in this study, many have already been shown to be involved in B cell proliferation, activation, and autoimmune diseases. IL-10 is a cytokine produced by various cell types, including activated T lymphocytes, B lymphocytes, and macrophages [26 ]. IL-10 can suppress cytokine production and several accessory cell functions by T-helper cell type 1 (Th1) cells, macrophages, and NK cells and is regarded as a potent suppressor of the effecter functions of these cells [26 ]. Conversely, IL-10 is a potent stimulator of B lymphocyte proliferation and differentiation [27 ] and is critically involved in regulating autoantibody-secreting B cell activities in SLE [28 ]. This is consistent with our observation that IL-10 is a downstream gene up-regulated by TALL-1 and its B cell activation receptor BAFF-R. It is possible that IL-10 is one of the effecter molecules in TALL-1-triggered B cell proliferation and lupus-like autoimmune diseases.

PBEF is a 52-kDa-secreted protein that is dramatically induced by pokeweed mitogen in peripheral blood leukocytes [29 ]. It has been shown that PBEF could enhance the pre-B cell colony-formation activity of stem-cell factor and IL-7 [29 ].

TALL-1 stimulation of B lymphocytes up-regulates expression levels of two chemokine genes, GCP-2 and LAG-1. GCP-2 [30 ], also called small, inducible cytokine subfamily B, member 6 (SCYB6) [31 ], is a member of the CXC chemokine family [32 33 34 35 ]. LAG-1 [36 ], also called small inducible chemokine A4 (SCYA4) [37 ] and Act-2 [38 ], is a member of the CC chemokine family and is the human counterpart of mouse macrophage inflammatory protein-1ß (MIP-1ß) [32 33 34 35 36 37 38 ]. Interestingly, the receptors for GCP-2 (CCR1 and CCR2) and the receptor for MIP-1ß (CCR5) are mostly expressed by Th1 cells and macrophages [32 33 34 35 ]. Gene knockout experiments have demonstrated that CCR2 is critically involved in experimental autoimmune encephalomyelitis [35 ]. As the macrophage-produced TALL-1 can activate B lymphocytes to produce GCP-2 and LAG-1, whose receptors are expressed by macrophages, it is possible that TALL-1-regulated expression of GCP-2 and LAG-1 is involved in functional interaction between macrophages and B lymphocytes.

PIM-2 is a protooncogene belonging to the PIM kinase family. PIM-2 is highly expressed in mitogen-stimulated hematopoietic cells and is induced by a variety of cytokines that also induce NF-{kappa}B [39 ]. PIM-2 collaborates with c-myc to promote progression of cell cycle [40 ] and to induce neonatal pre-B cell leukemia in transgenic mice [39 ]. Recently, it has been shown that PIM-2 is a NF-{kappa}B target gene at the pre-B to immature B cell transition [41 ]. As TALL-1 can activate NF-{kappa}B, it is not surprising that PIM-2 is identified as a downstream gene of TALL-1 in this study. Based on the known function of PIM-2, we speculate that PIM-2 is one of the downstream genes that is involved in TALL-1-induced B cell proliferation.

CD27L (CD70) is a member of the TNF family of ligands that binds to CD27. CD27L and CD27 are mostly expressed by activated lymphocytes, and their interaction plays a key role in T-dependent B cell responses [42 ].

Ferritin is an iron storage protein and is critically involved in iron homeostasis. Although it is not known how ferritin may be involved in TALL-1-triggered effects, it has been shown that serum ferritin is dramatically increased with the progression of SLE [43 , 44 ]. This is in good correlation with TALL-1, which is also increased with the progression of SLE [5 ].

Archain, also called coatomer delta subunit, is one component of the cytosolic protein complex called coatomer. Coatomer associates with Golgi nonclathrin-coated vesicles and is involved in vesicle transport and protein secretion [45 ]. It is possible that up-regulation of coatomer components such as archain may be necessary for TALL-1-triggered secretion of Igs and other related activities.

TFG was originally identified in human as the N-terminus of an oncogenic fusion protein TRK-T3, associated with papillary thyroid carcinoma [46 ]. An amino-terminal, coiled-coil domain of TFG is responsible for mediating oligomerization of the TRK-T3 oncoprotein, which results in constitutive activation of the TRK protein tyrosine kinase and oncogenesis [46 ]. DUSP5 is a dual-specific phosphatase, and the physiological functions of DUSP5 are not known. The involvement of TFG and DUSP5 in TALL-1 signaling needs to be further explored.

Our cDNA subtraction hybridization experiments also suggest that elongation factor 1 {alpha} is down-regulated by TALL-1. The functional significance of this observation is still unclear.

In conclusion, we have identified 10 genes up-regulated by TALL-1. Our findings provide important groundwork to understand the mechanisms of TALL-1-triggered, biological effects and to identify potential molecular targets for intervention of TALL-1-triggered diseases such as SLE.


   ACKNOWLEDGEMENTS
 
This work was supported by grants from the Ellison Medical Foundation, a National Institute of Health grant (1RO1 AI49992-01), the Arthritis Foundation, National Natural Science Foundation of China (#39925016), the Chinese "863" Program (#2001AA221281), and the Special Funds for Major State Basic Research of China (#G19990539).


   FOOTNOTES
 
L-G. X. and M. W. are co-first authors.

Received February 1, 2002; revised March 12, 2002; accepted March 27, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

  1. Shu, H. B., Hu, W. H., Johnson, H. (1999) TALL-1 is a novel member of the TNF family that is down-regulated by mitogens J. Leukoc. Biol. 65,680-683[Abstract]
  2. Schneider, P., MacKay, F., Steiner, V., Hofmann, K., Bodmer, J. L., Holler, N., Ambrose, C., Lawton, P., Bixler, S., Orbea, H., Valmori, D., Romero, P., Werner-Favre, C., Zubler, R. H., Browning, J. L., Tschopp, J. (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth J. Exp. Med. 189,1747-1756[Abstract/Free Full Text]
  3. Moore, P. A., Belvedere, O., Orr, A., Pieri, K., LaFleur, D. W., Feng, P., Soppet, D., Charters, M., Gentz, R., Parmelee, D., Li, Y., Galperina, O., Giri, J., Roschke, V., Nardelli, B., Carrell, J., Sosnovtseva, S., Greenfield, W., Ruben, S. M., Olsen, H. S., Fikes, J., Hilbert, D. M. (1999) BLyS: member of the tumor necrosis factor family and B cell stimulator Science 285,260-263[Abstract/Free Full Text]
  4. Mukhopadhyay, A., Ni, J., Zhai, Y., Yu, G. L., Aggarwal, B. B. (1999) Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-{kappa}B, and c-Jun NH2-terminal kinase J. Biol. Chem. 274,15978-15981[Abstract/Free Full Text]
  5. Gross, J. A., Johnston, J., Mudri, S., Enselman, R., Dillon, S. R., Madden, K., Xu, W., Parrish-Novak, J., Foster, D., Lofton-Day, C., Moore, M., Littau, A., Grossman, A., Haugen, H., Foley, K., Blumberg, H., Harrison, K., Kindsvogel, W., Clegg, C. H. (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease Nature 404,995-999[Medline]
  6. Laabi, Y., Gras, M. P., Carbonne, F., Brouet, J. C., Berger, R., Larsen, C. J., Tsapis, A. (1992) A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a maligant T cell lymphoma EMBO J. 11,3897-3904[Medline]
  7. Gras, M. P., Laabi, Y., Linares-Cruz, G., Blondel, M. O., Rigaut, J. P., Brouet, J. C., Leca, G., Haguenauer-Tsapis, R., Tsapis, A. (1995) BCMAp: an integral membrane protein in the Golgi apparatus of human mature B lymphocytes Int. Immunol. 7,1093-1106[Abstract/Free Full Text]
  8. Laabi, Y., Gras, M. P., Brouet, J. C., Berger, R., Larsen, C. J., Tsapis, A. (1994) The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectally transcribed Nucleic Acids Res. 22,1147-1154[Abstract/Free Full Text]
  9. von Bulow, G. U., Gram, R. J. (1997) NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily Science 278,138-141[Abstract/Free Full Text]
  10. Shu, H. B., Johnson, H. (2000) B cell maturation protein is a receptor for the TNF family member TALL-1 Proc. Natl. Acad. Sci. USA 97,9156-9159[Abstract/Free Full Text]
  11. Thompson, J. S., Schneider, P., Kalled, S. L., Wang, L., Lefevre, E. A., Cachero, T. G., MacKay, F., Bixler, S. A., Zafari, M., Liu, Z. Y., Woodcock, S. A., Qian, F., Batten, M., Madry, C., Richard, Y., Benjamin, C. D., Browning, J. L., Tsapis, A., Tschopp, J., Ambrose, C. (2000) BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population J. Exp. Med. 192,129-136[Abstract/Free Full Text]
  12. Marsters, S. A., Yan, M., Pitti, R. M., Haas, P. E., Dixit, V. M., Ashkenazi, A. (2000) Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI Curr. Biol. 10,785-788[Medline]
  13. Xia, X. Z., Treanor, J., Senaldi, G., Khare, S. D., Boone, T., Kelley, M., Theill, L. E., Colombero, A., Solovyev, I., Lee, F., McCabe, S., Elliott, R., Miner, K., Hawkins, N., Guo, J., Stolina, M., Yu, G., Wang, J., Delaney, J., Meng, S. Y., Boyle, W. J., Hsu, H. (2000) TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation J. Exp. Med. 192,137-144[Abstract/Free Full Text]
  14. Yan, M., Marsters, S. A., Grewal, I. S., Wang, H., Ashkenazi, A., Dixit, V. M. (2000) Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity Nat. Immunol. 1,37-41[Medline]
  15. Thompson, J. S., Bixler, S. A., Qian, F., Vora, K., Scott, M. L., Cachero, T. G., Hession, C., Schneider, P., Sizing, I. D., Mullen, C., Strauch, K., Zafari, M., Benjamin, C. D., Tschopp, J., Browning, J. L., Ambrose, C. (2001) BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF Science 293,2108-2111[Abstract/Free Full Text]
  16. Kanakaraj, P., Migone, T. S., Nardelli, B., Ullrich, S., Li, Y., Olsen, H. S., Salcedo, T. W., Kaufman, T., Cochrane, E., Gan, Y., Hilbert, D. M., Giri, J. (2001) BLyS binds to B cells with high affinity and induces activation of the transcription factors NF-{kappa}B and ELF-1 Cytokine 13,25-31[Medline]
  17. Macky, F., Woodcock, S. A., Lawton, P., Ambrose, C., Baetscher, M., Schneider, P., Tschopp, J., Browning, J. L. (1999) Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manisfestations J. Exp. Med. 190,1697-1710[Abstract/Free Full Text]
  18. Khare, S. D., Sarosi, I., Xia, X. Z., McCabe, S., Miner, K., Solovyev, I., Hawkins, N., Kelley, M., Chang, D., Van, G., Ross, L., Delaney, J., Wang, L., Lacey, D., Boyle, W. J., Hsu, H. (2000) Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice Proc. Natl. Acad. Sci. USA 97,3370-3375[Abstract/Free Full Text]
  19. Wang, H., Marsters, S. A., Baker, T., Chan, B., Lee, W. P., Fu, L., Tumas, D., Yan, M., Dixit, V. M., Ashkenazi, A., Grewal, I. S. (2001) TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice Nat. Immunol. 2,63263-63267
  20. Schiemann, B., Gommerman, J. L., Vora, K., Cachero, T. G., Shulga-Morskaya, S., Dobles, M., Frew, E., Scott, M. L. (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway Science 293,2111-2114[Abstract/Free Full Text]
  21. Yan, M., Wang, H., Chan, B., Roose-Girma, M., Erickson, S., Baker, T., Tumas, D., Grewal, I. S., Dixit, V. M. (2001) Activation and accumulation of B cells in TACI-deficient mice Nat. Immunol. 2,638-643[Medline]
  22. Xu, S., Lam, K. P. (2001) B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses Mol. Cell. Biol. 21,4067-4074[Abstract/Free Full Text]
  23. von Bulow, G. U., van Deursen, J. M., Bram, R. J. (2001) Regulation of the T-independent humoral response by TACI Immunity 14,573-582[Medline]
  24. Hatzoglou, A., Roussel, J., Bourgeade, M. F., Rogier, E., Madry, C., Inoue, J., Devergne, O., Tsapis, A. (2000) TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-{kappa}B, Elk-1, c-jun N-terminal kinase, and p38 mitogen-activated protein kinase J. Immunol. 165,1322-1330[Abstract/Free Full Text]
  25. Liu, Y., Xu, L., Opalka, N., Kappler, J., Shu, H. B., Zhang, G. (2002) Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands Cell 108,383-394[Medline]
  26. Moore, K. W., O’Garra, A., Waal Malefyt, R. D., Vieira, P., Mosmann, T. R. (1993) Interleukin 10 Annu. Rev. Immunol. 11,165-190[Medline]
  27. Rousset, F., Garcia, E., Defrance, C., Peronne, D. H., Hsu, R., Kastelein, K. (1992) IL-10 is a potent growth and differentiation factor for activated human B lymphocytes Proc. Natl. Acad. Sci. USA 89,1890-1893[Abstract/Free Full Text]
  28. Cross, J. T., Benton, H. P. (1999) The roles of interleukin-6 and interleukin-10 in B cell hyperactivity in systemic lupus erythaematosus Inflamm. Res. 48,255-261[Medline]
  29. Samal, B., Sun, Y., Stearns, G., Xie, C., Suggs, S., McNiece, I. (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor Mol. Cell. Biol. 14,1431-1437[Abstract/Free Full Text]
  30. Rovai, L. E., Herschman, H. R., Smith, J. B. (1997) Cloning and characterization of the human granulocyte chemotactic protein-2 gene J. Immunol. 158,5257-5266[Abstract]
  31. Froyen, G., Proost, P., Ronsse, I., Mitera, T., Haelens, A., Wuyts, A., Opdenakker, G., Van Damme, J., Billiau, A. (1997) Cloning, bacterial expression and biological characterization of recombinant human granulocyte chemotactic protein-2 and differential expression of granulocyte chemotactic protein-2 and epithelial cell-derived neutrophil activating peptide-78 mRNAs Eur. J. Biochem. 243,762-769[Medline]
  32. Baggiolini, M., Dewald, B., Moser, B. (1997) Human chemokines: an update Annu. Rev. Immunol. 15,675-705[Medline]
  33. Mackay, C. R. (2001) Chemokines: immunology’s high impact factors Nat. Immunol. 2,95-101[Medline]
  34. Luther, S. A., Cyster, J. G. (2001) Chemokines as regulators of T cell differentiation Nat. Immunol. 2,102-107[Medline]
  35. Gerard, C., Rollins, B. J. (2001) Chemokines and disease Nat. Immunol. 2,108-115[Medline]
  36. Baixeras, E., Roman-Roman, S., Jitsukawa, S., Genevee, C., Mechiche, S., Viegas-Pequignot, E., Hercend, T., Triebel, F. (1990) Cloning and expression of a lymphocyte activation gene (LAG-1) Mol. Immunol. 27,1091-1102[Medline]
  37. Brown, K. D., Zurawski, S. M., Mosmann, T. R., Zurawski, G. (1989) A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes J. Immunol. 142,679-687[Abstract]
  38. Lipes, M. A., Napolitano, M., Jeang, K. T., Chang, N. T., Leonard, W. J. (1988) Identification, cloning, and characterization of an immune activation gene Proc. Natl. Acad. Sci. USA 85,9704-9708[Abstract/Free Full Text]
  39. Allen, J. D., Verhoeven, E., Domen, J., van der Valk, M., Berns, A. (1997) Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc Oncogene 15,1133-1141[Medline]
  40. Shirogane, T., Fukada, T., Muller, J. M., Shima, D. T., Hibi, M., Hirano, T. (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis Immunity 11,709-719[Medline]
  41. Li, J., Peet, G. W., Balzarano, D., Li, X., Massa, P., Barton, R. W., Marcu, K. B. (2001) Novel NEMO/I{kappa}B kinase and NF-{kappa}B target genes at the pre-B to immature B cell transition J. Biol. Chem. 276,18579-18590[Abstract/Free Full Text]
  42. Jacquot, S. (2000) CD27/CD70 interactions regulate T dependent B cell differentiation Immunol. Res. 21,23-30[Medline]
  43. Lim, M. K., Lee, C. K., Ju, Y. S., Cho, Y. S., Lee, M. S., Yoo, B., Moon, H. B. (2001) Serum ferritin as a serologic marker of activity in systemic lupus erythaematosus Rheumatol. Int. 20,89-93[Medline]
  44. Nishiya, K., Hashimoto, K. (1997) Elevation of serum ferritin levels as a marker for active systemic lupus erythaematosus Clin. Exp. Rheumatol. 15,39-44[Medline]
  45. Cosson, P., Letourneur, F. (1997) Coatomer (COPI)-coated vesicles: role in intracellular transport and protein sorting Curr. Opin. Cell Biol. 9,484-487[Medline]
  46. Greco, A., Mariani, C., Miranda, C., Lupas, A., Pagliardini, S., Pomati, M., Pierotti, M. A. (1995) The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain Mol. Cell. Biol. 15,6118-6127[Abstract]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
A. Rongvaux, M. Galli, S. Denanglaire, F. Van Gool, P. L. Dreze, C. Szpirer, F. Bureau, F. Andris, and O. Leo
Nicotinamide Phosphoribosyl Transferase/Pre-B Cell Colony-Enhancing Factor/Visfatin Is Required for Lymphocyte Development and Cellular Resistance to Genotoxic Stress
J. Immunol., October 1, 2008; 181(7): 4685 - 4695.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
T. Luk, Z. Malam, and J. C. Marshall
Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity
J. Leukoc. Biol., April 1, 2008; 83(4): 804 - 816.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. M. Mills, G. Bonizzi, M. Karin, and R. C. Rickert
Regulation of late B cell differentiation by intrinsic IKK{alpha}-dependent signals
PNAS, April 10, 2007; 104(15): 6359 - 6364.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
W. W. Chen, D. C. Chan, C. Donald, M. B. Lilly, and A. S. Kraft
Pim Family Kinases Enhance Tumor Growth of Prostate Cancer Cells
Mol. Cancer Res., August 1, 2005; 3(8): 443 - 451.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. P.J. de Winther, E. Kanters, G. Kraal, and M. H. Hofker
Nuclear Factor {kappa}B Signaling in Atherogenesis
Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 904 - 914.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. Q. Ye, B. A. Simon, J. P. Maloney, A. Zambelli-Weiner, L. Gao, A. Grant, R. B. Easley, B. J. McVerry, R. M. Tuder, T. Standiford, et al.
Pre-B-Cell Colony-enhancing Factor as a Potential Novel Biomarker in Acute Lung Injury
Am. J. Respir. Crit. Care Med., February 15, 2005; 171(4): 361 - 370.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Zhang, L.-G. Xu, K.-J. Han, and H.-B. Shu
Identification of a ZU5 and Death Domain-containing Inhibitor of NF-{kappa}B
J. Biol. Chem., April 23, 2004; 279(17): 17819 - 17825.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. J. Fox, P. S. Hammerman, R. M. Cinalli, S. R. Master, L. A. Chodosh, and C. B. Thompson
The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor
Genes & Dev., August 1, 2003; 17(15): 1841 - 1854.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Wu, L.-G. Xu, Z. Zhai, and H.-B. Shu
SINK Is a p65-interacting Negative Regulator of NF-{kappa}B-dependent Transcription
J. Biol. Chem., July 11, 2003; 278(29): 27072 - 27079.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L.-G. Xu and H.-B. Shu
TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-{kappa}B Activation and IL-10 Production
J. Immunol., December 15, 2002; 169(12): 6883 - 6889.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xu, L.-G.
Right arrow Articles by Shu, H.-B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xu, L.-G.
Right arrow Articles by Shu, H.-B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS