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B1 p50 Is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-B2 p100 to p52 in Quiescent Mature B Cells1
Departments of
*
Pathology,
Microbiology and Immunology, and
Medicine, and
Cornell-Rockefeller University-Sloan-Kettering Institute Tri-Institutional MD-PhD Program, Weill Medical College of Cornell University, New York, NY, 10021;
¶ Albert Einstein College of Medicine, New York, NY 10461; and
|| Medical Research Council Center for Immune Regulation, Birmingham University, Birmingham, U.K.
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Abstract |
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B through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IB
characteristic of the classical NF-B pathway, albeit maintaining IB at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-B pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-xL in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-B pathways and selective downstream antiapoptotic genes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of BLyS receptors is largely restricted to B lineage cells (7, 12), with the exception of a subset of T cells (13). As is the case for most TNF family proteins, BLyS signaling activates NF-B in primary mouse B cells in vitro, p50 and RelB in particular (9). NF-B exists as an inactive dimer retained in the cytoplasm by inhibitors of NF-B (IBs). In the classical NF-B activation pathway, IB is degraded by the ubiquitin-proteasome pathway following phosphorylation by the IB kinase complex (IKK complex) in response to extracellular signals. This leads to nuclear translocation of active NF-B dimers consisting of various combinations of p65 (RelA), c-Rel (Rel), RelB, p50 (NF-B1), and p52 (NF-B2). Among them, p50 and p52 are processed from inactive precursors, p105 and p100, respectively (14).
More recently, p52 was shown to be activated not by IB degradation, but via processing of the p100 precursor which involves NF-B-inducing kinase (NIK) (15) and IKK (16). BLyS activates this alternative pathway in immature type 1 (T1) B cells generated by differentiation of bone marrow precursors in vitro and in total splenic B cells ex vivo (17), in a BLyS receptor 3 (BR3)-dependent manner (17, 18). Processing of p100 was independent of NF-B essential modulator (NEMO or IKK
), an essential component of the classical NF-B activation pathway, but p52, NIK, and BR3 are thought to be essential for transitional B cell survival in vitro and in short-term adoptive transfers (17). However, defective peripheral B cell development occurs in mice deficient in BLyS (6) or both p50 and p52 (19), but not in those lacking p52 or p50 alone (20, 21, 22) or harboring a mutation in NIK (23). This raises the possibility that the BLyS signals for B cell survival and development may be mediated by cooperative activation of the classical and alternative NF-B pathways.
We have addressed the activation of both NF-B pathways by BLyS in the context of survival of naive quiescent splenic B cells, which are critical for maintaining the mature B cell pool. We demonstrate that BLyS rapidly activates p50/p65 and promotes processing of p100 with delayed kinetics independent of p50. Moreover, p50 is temporally required to mediate BLyS signals for attenuation of quiescent mature B cell apoptosis and activation of Bcl-xL ex vivo.
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Materials and Methods |
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High density splenic B cells were isolated from 8- to 12-wk-old C57BL/6 (Taconic Farms, Germantown, NY), c-rel-/- (24), A1-a-/- (25), or p50(NF-B1)-/- (The Jackson Laboratory, Bar Harbor, ME) mice and their respective littermate controls as previously described (9). These cells were recovered from the 60–70% interface of a discontinuous Percoll gradient, and represent mature resting B cells arrested in G0/G1. They were cultured in vitro in the absence or presence of soluble recombinant human BLyS (5 ng/ml unless otherwise indicated, provided by Human Genome Sciences, Rockville, MD) also as described (9). In some cultures, cells were preincubated with cycloheximide (50 µg/ml; Sigma-Aldrich, St. Louis, MO), lactacystin (10 µM) or MG132 (20 µM; both from Calbiochem, La Jolla, CA), for 1 h before the addition of either 50 ng/ml BLyS or 10 µg/ml LPS (Sigma-Aldrich) for the time indicated. Apoptotic cells were detected by flow cytometry on a FACSCalibur using an Annexin VFITC apoptosis detection kit (Oncogene Research, Cambridge, MA).
EMSA
Preparation of whole cell extracts and analysis of NF-B DNA binding activity by EMSA were performed as previously described, using the H2K probe (9). For Ab supershifts, the cell extracts were preincubated with rabbit antisera against human NF-B p50, mouse RelB (Santa Cruz Biotechnology, Santa Cruz, CA), or human NF-B2 p52 (Upstate Biotechnology, Waltham, MA) for 30 min on ice before the addition of the radiolabeled probe. The DNA-protein complexes were resolved by electrophoresis on a native 5 or 6% polyacrylamide gel as indicated, in 1x TBE (25 mM Tris-Cl, pH 8.3, 25 mM boric acid, 0.5 mM EDTA) at 180 V. The gel was dried and analyzed by autoradiography.
Immunoblotting
Proteins in whole cell extracts (15–40 µg of protein, in equal amounts) were resolved by 10–15% SDS-PAGE, transferred to a polyvinylidene difluoride membrane and probed with the following Abs: rabbit antisera against human IB and IB
(Santa Cruz Biotechnology), mouse anti-human phospho-IB (Cell Signaling, Beverly, MA), human NF-B2 p52 (Upstate Biotechnology, Waltham, MA), human Bcl-xL, human Bak (BD PharMingen, San Diego, CA), mouse Bim (StressGen Biotechnologies, San Diego, CA); mouse anti-human phospho-IB (Cell Signaling), mouse anti-Bax (BD PharMingen); rat anti-A1 (26); hamster anti-mouse Bcl-2 and goat anti-actin (Santa Cruz Biotechnology). The blots were incubated with species-specific biotinylated secondary Abs and then streptavidin-conjugated HRP (Jackson ImmunoResearch Laboratories, West Grove, PA). The signals were revealed by ECL (Amersham Biosciences, Piscataway, NJ).
RNase protection assay (RPA)
Total RNA was isolated as previously described (27) and RPA was performed using a Riboquant kit (BD PharMingen). In brief, RNA (10 µg) was hybridized overnight to a mAPO-2 (mouse apoptosis) probe set containing [-32P]UTP-labeled antisense RNA transcripts. Following digestion of free probe and ssRNA with RNase A, the protected RNAs were resolved on a 5% denaturing polyacrylamide gel, analyzed by autoradiography, and quantified by phosphoimaging analysis. RNA loading was normalized to the protected fragment of the control L32 pseudogene.
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Results |
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BLyS activates p50 homodimers and RelB-containing dimers in primary quiescent B cells within 24 h of stimulation, as we have previously shown (9). Given that RelB is retained by p100 in the cytoplasm until it is released as p52/RelB dimers following p100 processing (28), activation of RelB-containing dimers suggests that BLyS may activate p100 processing in quiescent B cells. This was verified: p100 processing was enhanced by 2 h and increased with time of BLyS stimulation (Fig. 1A). Consistent with a precursor-product relationship, processing of p100 was followed by a progressive increase in p52 from 6 h onward (Fig. 1A). In quiescent B cells isolated from p50-/- mice, the level of p100 was significantly lower (Fig. 1B), presumably due to reduced synthesis because the p100 gene is a target of NF-B regulation (29). Despite this, BLyS increased p52 in p50-/- B cells to a level comparable to p50+/+ cells (Fig. 1B). Therefore, BLyS activates p100 processing in quiescent mature splenic B cells independent of p50.
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B DNA binding activity (Fig. 1C, lanes 9–15). Moreover, activation of p52/RelB requires BLyS, although the p52/p52 complex could be activated by incubation in the complete RPMI 1640 medium alone (Fig. 1C, compare lanes 10–12). Our results are consistent with NEMO-independent activation of p100 processing by BLyS in immature T1 B cells and total splenic B cells in vitro (17), and further demonstrate that BLyS promotes p100 processing, specifically the p52/RelB DNA binding activity, in quiescent mature B cells independent of p50.
BLyS rapidly activates p50/p65 and induces IB phosphorylation without apparent IB degradation
Having ascertained that BLyS promotes p100 processing in quiescent mature B cells, we next addressed the temporal relationship between activation of the alternative and classical NF-B pathways. The NF-B DNA binding activity present in freshly isolated resting B cells was first reduced by a 12-h incubation in complete medium (Fig. 2A). BLyS rapidly and transiently activated the p50/p65 DNA binding activity, which was detectable by 30 min, peaking by 2 h and declined by 6 h. This differed considerably from the delayed, but sustained, activation of RelB-containing complexes (p50(p52)/RelB) and p50 homodimers, whose binding was increased around 2 h and after 6 h, respectively (Fig. 2A). Thus, BLyS activates various NF-B dimers with distinct kinetics and duration, and activation of p50(p52)/RelB is coincidental with p100 processing and preceded by the transient activation of p50/p65.
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B is degraded by the proteasome-mediated mechanism characteristic of the classical NF-B activation pathway. However, the IB levels did not change throughout 12 h of BLyS stimulation (Fig. 2B), and the IB levels were similarly maintained (Fig. 2C). This suggests two possibilities: either IB is not subject to proteasome-mediated degradation in response to BLyS, or proteasome-mediated degradation of IB is counterbalanced by IB synthesis at steady state.
Given that IB degradation is initiated by its phosphorylation through the IKK complex (14), we characterized phosphorylation of IB by immunoblotting with an Ab specific for phosphorylated serine 32 and serine 36 of IB (Fig. 3A). IB phosphorylation is constitutive in freshly isolated quiescent B cells (data not shown), and markedly reduced by incubation in complete medium for 12 h (Fig. 3A, lane 1). Inhibition of the proteasome by either lactacystin or MG132 for 3 h prominently increased the levels of p-IB (Fig. 3A, lanes 2 and 5), indicating that the proteasome mediates the degradation of IB phosphorylated in response to components in the medium. However, the steady state IB level still remained constant. This suggests that preservation of p-IB that would have been otherwise degraded by the ubiquitin-proteasome pathway in quiescent mature B cells did not result in a detectable change in IB levels.
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B (Fig. 3A, compare lanes 4 and 1). Confirming these data, EMSA results show that there is no difference in p50/p65 DNA binding activity with or without BLyS when MG132 or lactacystin is present (data not shown). Either IB is not phosphorylated in response to BLyS, or BLyS-mediated IB phosphorylation is masked by the high levels of p-IB accumulated in the absence of proteolysis. To distinguish these two possibilities, the p-IB level in quiescent B cells was reduced to a negligible level by incubation in RPMI 1640 medium containing 0.5% FCS for 12 h before BLyS was added (Fig. 3B). Phosphorylation of IB was rapidly induced by BLyS, detectable by 10 min and increased with time, although it was also not accompanied by changes in IB levels. Together with the rapid enhancement of p50/p65 DNA binding activity (Fig. 2A) in the context of a constant level of IB (Fig. 3), this result suggests that BLyS signaling leads to rapid phosphorylation of a fraction of the pre-existing IB, which turns over by proteasome-mediated degradation.
The increase of IB by BLyS requires protein synthesis
Next, we addressed the possibility that the steady state IB levels are maintained in quiescent B cells in BLyS signaling by balancing IB degradation with new synthesis (Fig. 4). To inhibit protein synthesis, quiescent B cells were incubated with cycloheximide for 1 h in complete medium before BLyS was added (Fig. 4A). As a control, stimulation with LPS was performed in parallel (Fig. 4B). In the presence of cycloheximide, the IB levels remained unchanged for up to 2 h of BLyS stimulation, when normalized to the actin loading controls (Fig. 4A). Stimulation with BLyS alone led to a modest but appreciable increase in IB (Fig. 4A, compare lanes 10 and 11), suggesting that protein synthesis might be required to increase IB levels by BLyS. The IB level was markedly reduced in response to LPS as expected; however, this was not significant until 2 h of LPS stimulation and was more severe when protein synthesis was inhibited (Fig. 4B, lanes 8–10). Taken together, these data suggest that the extent of NF-B activation through the classical pathway is intrinsically modest in the metabolically restricted milieu of quiescent B cells, even by a strong NF-B activator such as LPS.
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B synthesis and phosphorylation confirmed that protein synthesis was required to increase the IB levels in BLyS signaling (Fig. 4C). Moreover, the BLyS-mediated enhancement of IB phosphorylation was partially insensitive to cycloheximide, consistent with phosphorylation of preexisting IB (Fig. 4C, compare lanes 2 and 3), and partially sensitive to cycloheximide (Fig. 4C, compare lanes 3 and 4), suggesting phosphorylation of newly translated IB.
NF-B p50 is temporally required for BLyS protection of resting B cells from apoptosis
Having established that p50/p65 was activated by BLyS (Fig. 2A), we asked whether p50 was required for the BLyS survival signals in quiescent B cells isolated from p50-/- mice (Fig. 5A). c-rel-/- B cells were used as a control because BLyS did not activate c-Rel-containing complexes (Fig. 2A). Quiescent B cells lacking p50 were more prone to apoptosis ex vivo than their wild-type littermate controls (Fig. 5A), in agreement with an earlier report (30). Importantly, the absence of p50 severely impaired BLyS protection of quiescent B cells from apoptosis in the first 24 h, but not after prolonged stimulation with BLyS (48 h) (Fig. 5A). By contrast, the c-rel+/+ and c-rel-/- B cells were equally protected from apoptosis by BLyS, despite their propensity to undergo apoptosis in the absence of BLyS (Fig. 5B). Thus, p50, but not c-Rel, is temporally required to mediate BLyS signals for the attenuation of quiescent B cell apoptosis ex vivo.
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Bcl-xL, but not Bcl-2, was marginally activated in quiescent B cells by 24 h of BLyS stimulation (9). The distinct kinetics with which BLyS activates NF-B prompted us to examine the time course of BLyS regulation of Bcl-xL and A1 (Bfl-1), two NF-B target antiapoptotic genes of the Bcl-2 family, and their role in mediating the BLyS survival signals. There are three mouse homologues (A1-a, -b, and -d) of the human Bfl-1 gene (now renamed A1-a) that share 97% nucleotide identity (31). RPAs showed that in quiescent B cells, A1 and Bcl-xL RNAs were increased 3- to 5-fold (the probe detected all three mouse A1 RNA species) within 6 h of BLyS stimulation (Fig. 6, A and B), in agreement with the semiquantitative PCR analysis of mature B cells (32). However, activation of Bcl-xL and A1 by BLyS is both transient, as it declined by 24 h (Fig. 6, A and B). The proapoptotic Bak and Bax RNAs were marginally increased (Fig. 6, A and B) whereas the Bcl-2 and Bad RNA levels were below detection (data not shown). Therefore, BLyS preferentially and transiently increases the steady state levels of A1 and Bcl-xL RNAs.
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B to A1-a activation were limited to the analysis of A1 RNA. In any case, quiescent B cells isolated from A1-a-/- mice (25) were not predisposed to apoptosis ex vivo, and were protected from apoptosis by BLyS as efficiently as their wild-type counterparts (Fig. 6D). This finding is consistent with normal B cell development in A1-a-deficient mice (25, 33). Although it remains possible that an A1-a deficiency is compensated for by A1-b or A1-d, at least one of the mouse A1 genes is dispensable for protection of quiescent B cells from apoptosis by BLyS. By contrast, the Bcl-xL protein was elevated by BLyS stimulation, appreciable by 6 h, peaking by 12 h, and declined by 24 h (Fig. 7A). This correlated with the time course of increase in Bcl-xL RNA (Fig. 6, A and B). It was specific to Bcl-xL, because there was no change in Bcl-2 or other proapoptotic proteins such as Bak, Bax, BimEL, and BimL (Fig. 7A). Thus, BLyS specifically and transiently up-regulates Bcl-xL RNA with a corresponding increase in Bcl-xL protein in quiescent B cells. The initial dependence on p50 for mediating BLyS survival signals in quiescent B cells (Fig. 5A) correlated with transient activation of Bcl-xL (Figs. 6, A and B, and 7A), further suggesting that p50 may be required for BLyS activation of Bcl-xL. Indeed, BLyS failed to increase the Bcl-xL protein in B cells lacking p50, but not c-rel (Fig. 7, B and C). These results identify Bcl-xL as a target of p50 activation by BLyS.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B signaling pathways with distinct kinetics in quiescent mature B cells, and that p50 is transiently required for the activation of Bcl-xL and attenuation of quiescent B cell apoptosis ex vivo. Thus, BLyS is a physiologic cytokine that activates both NF-B signaling pathways in quiescent mature B cells, much like CD40 does in activated B cells (34). This raises important questions relating to the developmental stage specificity with which BLyS activates the two NF-B signaling pathways, the precise mechanisms by which BLyS activates these two pathways, and the target genes that mediate the survival signals in quiescent mature B cells. BLyS signaling in quiescent mature B cells
We have focused on BLyS signaling in quiescent mature B cells, as the maintenance of this population is critical for peripheral B cell homeostasis and tolerance. BLyS is absolutely required for peripheral B cell development (5, 6). But, it was in quiescent mature splenic B cells, of which 
85% express the mature CD23high/AA4.1low mature B cell phenotype (32), that BLyS was first demonstrated to act primarily through attenuation of apoptosis independent of the cell cycle (9). Subsequent studies expanded the repertoire of BLyS target cells, at least ex vivo, to include immature T2 B cells (10) and the less mature T1 B cells generated by in vitro differentiation of bone marrow precursors (17). Together with the present study, these results demonstrate that BLyS ensures B cell maturation by attenuating apoptosis of B cells at all stages during peripheral development, including mature B cells.
The range of BLyS action further extends to include activated B cells generated by CD40 ligand activation in vitro and in response to T cell-dependent and -independent Ags in vivo (Ref.9 and X. Huang and S. Chen-Kiang, unpublished observations) as well as extrafollicular plasmablasts (11). BLyS appears to antagonize the Ag receptor-mediated apoptotic pathway, given that BLyS was initially identified as a costimulator for anti-IgM (1) and could protect an immature B cell line WEHI 231 from Ag receptor-induced apoptosis in vitro (18). However, the Ag receptor is no longer expressed on terminally differentiated, Ab-secreting plasma cells, which are subject to TRAIL-mediated killing (35). Whether the terminally differentiated, Ab-secreting plasma cells are direct protected by BLyS is an interesting subject to follow, as this would have implications for the generation of long- and short-lived plasma cells in an Ab response.
BLyS activates both NF-B pathways in quiescent mature B cells
Primary quiescent B cells are subject to fewer compounding NF-B activation signals associated with cycling B cells. BLyS activates the alternative NF-B signaling pathway in quiescent mature B cells independent of the classical NF-B pathway, as evidenced by the ability of BLyS to promote p50-independent processing of p100 to p52 and activate sustained formation of the p52/RelB complex (Fig. 1). This is reminiscent of BLyS activation of p52 in immature T1 B cells, which does not require NEMO, an essential component of the classical NF-B pathway (17). In both cases, activation of p52 by BLyS is delayed (Fig. 2) (17) relative to activation of p50/p65 in the classical NF-B pathway (Fig. 2A). On the basis that BLyS induces a drastic reduction of p100 (Fig. 1, A and B) in the quiescent splenic B cell population composed mainly of mature B cells, BLyS must activate p100 processing in quiescent mature B cells.
Preceding p52 activation, BLyS activates the classical NF-B pathway in quiescent mature B cells, as demonstrated by the rapid activation of the p50/p65 DNA binding activity (Fig. 2A), and the phosphorylation of IB within minutes of BLyS treatment (Fig. 3B). This differs from BLyS signaling in immature T1 B cells, where only activation of the alternative NF-B pathway was observed (17). However, despite proteasome-mediated degradation of phosphorylated IB (Fig. 3A) the level of IB did not change at steady state in response to BLyS in quiescent mature B cells (Figs. 2B and 3). The time course of p50/p65 activation (Fig. 2A) and the partial dependence on protein synthesis for IB phosphorylation (Fig. 4C) suggests that BLyS induces phosphorylation of both pre-existing and newly synthesized IB. On this basis, we favor the possibility that BLyS activates only a fraction of IB, whose destruction is counterbalanced by new synthesis in quiescent mature B cells. Consistent with this notion, activation and destruction of IB is modest even by LPS, and the IB level is also sustained in response to BLyS (Figs. 2 and 4). Taken together, our data demonstrate that BLyS activates the classical NF-B pathway with distinct features unique to the metabolically restricted quiescent mature B cells.
The expression of the three BLyS receptors, BR3, B cell maturation Ag (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), is distinct during peripheral B cell development; mature B cells express markedly higher levels of BR3 as well as the inhibitory TACI (36) compared with immature T1 B cells (32). It is possible that BR3 mediates the BLyS signals for p100 processing in mature B cells, given its essential role in peripheral B cell development (5, 6) and in the activation of p100 processing in immature T1 B cells (17, 18). It is tempting to postulate that above a threshold, signaling through BR3 leads to activation of the classical NF-B pathway in addition to the alternative pathway and that the inhibitory TACI receptor functions to attenuate NF-B activation. This remains to be determined.
p50 is transiently required to mediate BLyS survival signals in quiescent mature B cells
p50 is required for B cell survival ex vivo (Fig. 5A) (30). Activation of the classical pathway in quiescent mature B cells has a functional consequence as p50 is transiently required to mediate BLyS survival signals (Fig. 5A) and activate Bcl-xL (Fig. 7). Regulation of Bcl-xL by BLyS, at both RNA and protein levels, is specific given the lack of regulation of Bcl-2 (Fig. 7), the A1 proteins despite enhancement of A1 RNAs (Fig. 6), and Bcl-2 family genes (Figs. 6 and 7). Bcl-xL is a target of NF-B (37). The strict correlation between transient Bcl-xL activation (Figs. 6 and 7) and p50-dependent attenuation of apoptosis by BLyS (Fig. 5) suggests that p50 mediates the BLyS survival signals through activation of Bcl-xL.
Our results contrast and complement the recent findings by Claudio et al. (17) that p52 is required to mediate BLyS survival signals in T1 B cells where Bcl-2, but not Bcl-xL, was activated. p50 has been reported to be essential for marginal zone B cell development (38) where BLyS is believed to play a crucial role (39). Collectively, these results imply a developmental specificity by which BLyS activates the two NF-B signaling pathways and the downstream Bcl-2 and Bcl-xL genes for B cell survival. The two NF-B activation pathways are likely to have overlapping functions, because the B cell developmental defect observed in BLyS- or BR3-deficient mice (5, 6, 7, 8) is recapitulated by targeting both p50 and p52 (19), but not one or the other alone (20, 21, 22). Based on the distinct time course with which the two NF-B pathways are activated and the transient requirement for p50 to mediate BLyS signals, it seems possible that the two NF-B signaling pathways also function in concert within the same quiescent mature B cells to maintain peripheral mature B cell homeostasis.
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Acknowledgments |
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Footnotes |
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2 E.N.H. and R.K.G.D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Selina Chen-Kiang, Department of Pathology, C-338, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. E-mail address: sckiang{at}mail.med.cornell.edu
4 Abbreviations used in this paper: BLyS, B lymphocyte stimulator; BAFF, B cell activating factor belonging to the TNF family; IB, inhibitor of NF-B; IKK, IB kinase; NIK, NF-B inducing kinase; BR3, BLyS receptor 3; NEMO, NF-B essential modulator; RPA, RNase protection assay; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor.
Received for publication March 4, 2003. Accepted for publication May 16, 2003.
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L. S. Treml, G. Carlesso, K. L. Hoek, J. E. Stadanlick, T. Kambayashi, R. J. Bram, M. P. Cancro, and W. N. Khan TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells J. Immunol., June 15, 2007; 178(12): 7531 - 7539. [Abstract] [Full Text] [PDF]
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S. K. Chang, B. K. Arendt, J. R. Darce, X. Wu, and D. F. Jelinek A role for BLyS in the activation of innate immune cells Blood, October 15, 2006; 108(8): 2687 - 2694. [Abstract] [Full Text] [PDF]
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C. O. Jacob, L. Pricop, C. Putterman, M. N. Koss, Y. Liu, M. Kollaros, S. A. Bixler, C. M. Ambrose, M. L. Scott, and W. Stohl Paucity of Clinical Disease despite Serological Autoimmunity and Kidney Pathology in Lupus-Prone New Zealand Mixed 2328 Mice Deficient in BAFF J. Immunol., August 15, 2006; 177(4): 2671 - 2680. [Abstract] [Full Text] [PDF]
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J. P. Miller, J. E. Stadanlick, and M. P. Cancro Space, Selection, and Surveillance: Setting Boundaries with BLyS. J. Immunol., June 1, 2006; 176(11): 6405 - 6410. [Abstract] [Full Text] [PDF]
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L. Fu, Y.-C. Lin-Lee, L. V. Pham, A. Tamayo, L. Yoshimura, and R. J. Ford Constitutive NF-{kappa}B and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas Blood, June 1, 2006; 107(11): 4540 - 4548. [Abstract] [Full Text] [PDF]
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 A. Craxton, K. E. Draves, A. Gruppi, and E. A. Clark BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway J. Exp. Med., November 21, 2005; 202(10): 1363 - 1374. [Abstract] [Full Text] [PDF]
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 T. Yamada, K. Zhang, A. Yamada, D. Zhu, and A. Saxon B Lymphocyte Stimulator Activates p38 Mitogen-Activated Protein Kinase in Human Ig Class Switch Recombination Am. J. Respir. Cell Mol. Biol., May 1, 2005; 32(5): 388 - 394. [Abstract] [Full Text] [PDF]
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 M. D. Morrison, W. Reiley, M. Zhang, and S.-C. Sun An Atypical Tumor Necrosis Factor (TNF) Receptor-associated Factor-binding Motif of B Cell-activating Factor Belonging to the TNF Family (BAFF) Receptor Mediates Induction of the Noncanonical NF-{kappa}B Signaling Pathway J. Biol. Chem., March 18, 2005; 280(11): 10018 - 10024. [Abstract] [Full Text] [PDF]
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X. Huang, M. Di Liberto, A. F. Cunningham, L. Kang, S. Cheng, S. Ely, H.-c. Liou, I. C. M. MacLennan, and S. Chen-Kiang Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1 PNAS, December 21, 2004; 101(51): 17789 - 17794. [Abstract] [Full Text] [PDF]
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Y. Sasaki, S. Casola, J. L. Kutok, K. Rajewsky, and M. Schmidt-Supprian TNF Family Member B Cell-Activating Factor (BAFF) Receptor-Dependent and -Independent Roles for BAFF in B Cell Physiology J. Immunol., August 15, 2004; 173(4): 2245 - 2252. [Abstract] [Full Text] [PDF]
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B. Zarnegar, J. Q. He, G. Oganesyan, A. Hoffmann, D. Baltimore, and G. Cheng Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-{kappa}B activation pathways PNAS, May 25, 2004; 101(21): 8108 - 8113. [Abstract] [Full Text] [PDF]
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 W Stohl A therapeutic role for BLyS antagonists Lupus, May 1, 2004; 13(5): 317 - 322. [Abstract] [PDF]
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B. He, A. Chadburn, E. Jou, E. J. Schattner, D. M. Knowles, and A. Cerutti Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/BLyS and APRIL J. Immunol., March 1, 2004; 172(5): 3268 - 3279. [Abstract] [Full Text] [PDF]
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