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B
Degradation Mechanisms Mediates Constitutive NF-B Activation in Mature B Cells1
*
Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53792; and
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B/Rel transcription
factors occurs via proteasome-dependent degradation of an associated
inhibitor, termed IB
. Mature B lymphocytes constitutively express
nuclear NF-B, which is important for their long-term survival. The
intrinsic mechanisms by which B cells constitutively activate NF-B
are unknown. In this paper we demonstrate that maintenance of NF-B
activity in primary B cells is mediated by a novel calcium-dependent,
but proteasome-independent, mechanism. Moreover, we show that
differentiation of conditionally transformed pre-B cells is accompanied
by a switch from proteasome-dependent to proteasome-independent
degradation of IB. Our findings indicate that IB
degradation mechanisms are dynamic during B cell development, and
ultimately establish constitutive NF-B activity in mature B
lymphocytes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or 
)
(1). This developmental program is regulated primarily at
the level of gene expression by the action of nuclear transcription
factors, including NF-B, which is composed of a dimeric combination
of Rel-homology proteins (2). In most cells, NF-B is
maintained as an inactive cytoplasmic complex due to its sequestration
by inhibitory proteins, such as IB and IBß (2).
A broad panel of extracellular stimuli (e.g., cytokines) activate
latent NF-B complexes by inducing proteasome-mediated degradation of
IB, which allows for translocation of Rel dimers into the nucleus
(2, 3). In contrast to most cell types, mature B cells
constitutively express nuclear NF-B, primarily in the form of
c-Rel/p50 heterodimers (4, 5, 6). This constitutive NF-B
activity is believed to play critical roles in the development of B
lymphocytes because it controls stage-specific expression of genes
encoding Ig (7, 8), Oct-2 (9), p50/p105
(4), c-Rel (10), and IB
(11). In addition, NF-B activity has been implicated in
promoting the survival of splenic B cells (12, 13), as
well as the capacity of B cells to proliferate (14, 15).
Despite these findings, the biochemical mechanisms that lead to
constitutive NF-B activation in developing B cells remains largely
undefined.
The finding that NF-B activation by distinct signals requires
proteasome-mediated degradation of IB led to the notion that
constitutive NF-B activity in B cells may simply result from a high
basal rate of IB by proteasomes. In contrast to this hypothesis,
we show that the primary mechanism for constitutive NF-B activation
in primary and transformed B cells is a novel calcium-dependent, but
proteasome-independent, pathway. Furthermore, we provide evidence that
a previously unprecedented switch of IB degradation mechanisms
mediates developmental establishment of constitutive NF-B activity
in B lymphocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine immature B (WEHI231, IgM+/IgD-) and mature B (WEHI279: IgM+/IgD+ nonsecreting) cell lines were obtained from American Type Culture Collection (Manassas, VA). WEHI231 cells were maintained in RPMI 1640 medium (Cellgro; Mediatech, Herdon, VA) supplemented with 10% FBS (HyClone Laboratory, Logan, UT), 5 x 10-5 M 2-ME, 1250 U penicillin G (Sigma, St. Louis, MO), and 0.5 mg/ml streptomycin sulfate (Sigma). The pre-B cell line transformed with a temperature-sensitive v-Abl oncoprotein (103/BCL 2-4 v-ablts, here referred to as ts-abl)3 was provided by Dr. N. Rosenberg (Tufts University, Medford, MA) and maintained in the above medium with G418 at 34.5°C. WEHI279 cells were grown in DMEM medium (Cellgro; Mediatech) supplemented with the above additives.
Chemicals
N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), DMSO, bacterial LPS (from Escherichia coli serotype 055:B5), ionomycin, and EGTA were purchased from Sigma. 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) was purchased from NovaBiochem (San Diego, CA). MG132 was purchased from Peptides International (Louisville, KY). Lactacystin was provided by Dr. E. J. Corey (Harvard University). The stock solutions were prepared as described previously (16).
Preparation and fluorescent activated cell sorting of primary splenocytes
To minimize potential in vitro activation of NF-B during cell
preparation (17), all isolation procedures were performed
at 4°C or on ice. Spleens isolated from 1- to 2-mo-old female C57BL/6
mice housed at the pathogen-free University of Wisconsin Comprehensive
Cancer Center Animal Facility were kept on ice, single cells were
manually released, and RBCs were hypotonically lysed with ice-cold
water followed by immediate isotonic adjustment with ice-cold 10x PBS.
Following filtration, total splenocytes were pelleted by rapid
centrifugation. Approximately 60% of splenocyte preparations were B
cells, whereas 
30% were T cells as judged by staining with
FITC-conjugated anti-IgM (R6-60.2; PharMingen, San Diego, CA) and
PE-conjugated anti-Thy1.2 (53-2.1; PharMingen) Abs followed by
analyses with FACStarPlus. To purify T- and
B-rich populations, splenocytes were stained as above with the
anti-Thy1.2 Ab and Thy1.2-positive and -negative cells were sorted
at 4°C. The B cell contents in these populations were <1% and
>90%, respectively. To examine the effect of various inhibitors,
splenocytes were resuspended 107 cells per ml in
the presence of inhibitors and incubated in a 37°C incubator for
indicated periods while gently mixed.
EMSA and Western blot analysis
Nuclear extracts preparation, the Ig intronic B
(Ig-B) probe, and conditions for EMSA were as previously
described (16). Sample preparation for Western blot
analysis was as described previously (16), and development
was via the enhanced chemiluminescence (ECL) procedure (Amersham,
Arlington Heights, IL). Anti-IB was purchased from Santa Cruz
Biotechnology (Santa Cruz, CA; C21) and anti--tubulin was from
Calbiochem (La Jolla, CA). Western blots were scanned with a Bio-Rad
(Richmond, CA) model GS-670 scanner and band intensities were
quantified using the Molecular Analyst program provided by the scanner
supplier (Bio-Rad).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activity in primary splenocytes
and B cell lines is calcium-dependent, but proteasome-independent
Inducible activation of NF-B is controlled by sequential
posttranslational modifications of IB ultimately leading to its
degradation by 26S proteasomes to liberate free NF-B. Consequently,
proteasome inhibitors, including ALLN, MG132, and lactacystin,
efficiently block IB degradation and NF-B activation (2, 3). However, these proteasome inhibitors were ineffective at
reducing constitutive NF-B activity levels in WEHI231 immature B
cells (Fig. 1
A, lanes
9–13). This is consistent with their inability to block high
IB turnover in these cells (16). Similarly, ALLN had
no effect on NF-B activity in the WEHI279 mature B cell line (Fig. 1A, lane 16). The lack of effects of proteasome inhibitors
was not due to a lack of their inhibitor efficacy in vivo, because they
can efficiently block basal IBß degradation as well as
LPS-inducible IB degradation and NF-B activation in these B
cells (16). In contrast, nuclear NF-B levels (Fig. 1A, lanes 7 and 15) and IB
degradation (data not shown; Ref. 16) were dramatically
diminished in both B cell lines by the intracellular and extracellular
calcium chelators BAPTA-AM and EGTA, respectively. The specificity of
these responses for calcium was demonstrated by their reversibility
with the calcium ionophore, ionomycin (Fig. 1A, lane 6).
Ionomycin alone did not augment basal NF-B activity levels
(lanes 1–5), indicating that increases in free
calcium are not sufficient to further activate the mechanisms involved
in the regulation of constitutive NF-B activity. Calcium chelators
do not nonspecifically prevent the proteasome-dependent activation
mechanism because LPS-inducible activation of NF-B in the B cell
lines is not affected by these agents (16). These results
indicate that the signaling pathway controlling constitutive NF-B
activity in transformed B cell lines relies on calcium regulation
without the involvement of IB degradation by a conventional
proteasome pathway.
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B activity in vivo, we isolated primary B lymphocytes from murine
spleen while minimizing the potential in vitro activation
(17) by maintaining the isolation procedures at 4°C. In
agreement with prior reports (5, 6), we found that the
majority of constitutive NF-B DNA-binding activity observed in
primary splenocytes is derived from the B cell compartment (data not
shown). Initially, primary splenocytes were cultured with proteasome
inhibitors or calcium chelators and nuclear extracts were analyzed by
EMSA for NF-B activity (Fig. 1
B). Consistent with our
observations in transformed B cells, relatively high doses of the
proteasome inhibitor MG132 (up to 20 µM) failed to reduce
constitutive NF-B activity in these primary cells (Fig. 1B, lanes 8 and 13). High doses of the
proteasome inhibitors ALLN (up to 100 µM) and lactacystin (up to 100
µM) also were ineffective (data not shown). In sharp contrast,
BAPTA-AM with or without EGTA efficiently reduced constitutive NF-B
levels in the primary splenocytes (Fig. 1B, lanes 5,
7, 10, and 12). Inhibitory effects of calcium chelators
were time-dependent (Fig. 1B), indicating that nuclear
NF-B in primary B cells has a relatively short half-life as in
WEHI231 cells (16). Thus, the spectrum of chemical
inhibitors that block constitutive NF-B activity in primary B cells
is identical to that observed in transformed B cells. These findings
indicate that a calcium-dependent, but proteasome-independent, pathway
is the primary mechanism that governs constitutive NF-B activity in
mature B lymphocytes.
Regulation of NF-B switches between proteasome-dependent and
-independent pathways during maturation of pre-B cells
Our new observations suggest that both primary and transformed B
cells possess an inherent mechanism to maintain nuclear NF-B
activity through a unique proteasome-independent pathway. However,
because a large body of data indicates that inducible activation of
latent NF-B complexes requires the action of proteasomes, our
observations led us to question whether the latent complexes in pre-B
cells are activated via a proteasome-dependent or -independent
mechanism during their maturation. To answer this question, we
monitored NF-B regulation in a pre-B cell line (103/BCL 2-4
v-ablts, here referred to as ts-abl) that
is conditionally transformed with a temperature-sensitive version of
the v-Abl tyrosine kinase (18). Previous studies showed
that incubation of these cells at the nonpermissive temperature is
accompanied by rapid induction of nuclear NF-B, Ig gene
expression, Ig gene rearrangement, and surface expression of IgM,
all hallmarks of immature B cell phenotype (18, 19). Thus,
this experimental system bypasses the need for extracellular stimuli to
activate NF-B and permits an assessment of
differentiation-associated molecular processes.
Time-course experiments revealed that in ts-abl cells, NF-B can be
induced as early as 1 h after the temperature shift (Fig. 2A, lane 2). The amount of
NF-B activity increases with time (lanes 2–9) due
to the appearance of complexes containing c-Rel and RelA (8, 18). Unlike our expectations based on above data using primary
and transformed B cells, pre-treatment of ts-abl cells with MG132
before the temperature shift efficiently blocked NF-B induction
(Fig. 2, B and C). Similarly, ALLN and
lactacystin were able to block NF-B induction in ts-abl cells (data
not shown). Unlike LPS stimulation of pre-B or B cell lines
(16), BAPTA-AM with or without EGTA also completely
prevented NF-B induction in this system (Fig. 2B,
lanes 4 and 5; others not shown). These
observations demonstrate that induction of NF-B activity in ts-abl
cells following the temperature shift is contingent on both proteasome
activity and free calcium.
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B activity in
ts-abl cells contrasts with that involved in the maintenance of NF-B
activity in primary and transformed B cells. These findings suggest the
possibility that developmental progression from the pre-B to mature B
cell stages might be accompanied by a biochemical transition from
proteasome-dependent to -independent mechanisms of NF-B regulation.
To directly test this possibility, we first maintained NF-B activity
in ts-abl cells by incubating them at the nonpermissive temperature for
6 or 24 h and subsequently exposed them to inhibitory compounds.
Under this experimental setting, the proteasome inhibitors MG132 (Fig. 3A, lanes 3–6), ALLN, and
lactacystin (data not shown) were unable to reverse constitutive
NF-B activity, even though these inhibitory compounds could
completely block initial induction of NF-B activity. Similar to our
results with primary B cells, we found that calcium chelators could
impose a dose-dependent inhibition on constitutive NF-B activity in
ts-abl cells (Fig. 3B, lanes 3–10). These
results suggest that B cells employ distinct biochemical mechanisms for
the induction (proteasome-dependent) and maintenance
(proteasome-independent) of NF-B activation during their
development.
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B degradation pathways mediates the shift of
NF-B regulation during differentiation of ts-abl cells
Our findings suggest an unprecedented model of NF-B regulation
in which the requirement of proteasome activity changes during pre-B to
mature B cell development. Because the primary target for proteasome
action is the inhibitor IB, we also measured levels of IB
in ts-abl cells during the initial induction and later maintenance
phases to examine whether distinct IB degradation mechanisms
mediate the changes in NF-B regulation. For this purpose, these
cells were pretreated with proteasome inhibitors or calcium chelators
together with the protein synthesis inhibitor cycloheximide for 30 min
and then incubated at 39.5°C for an additional hour to induce NF-B
activity. Western blot analyses of total cell extracts showed decreased
levels of IB proteins during the initial induction of NF-B
activity in ts-abl cells (Fig. 4A, upper panel, lane
2). Consistent with our EMSA data, the loss of IB could be
prevented by proteasome inhibitors (Fig. 4A, upper panel, lanes
3 and 4) and the calcium chelator, BAPTA-AM
(lane 5), but not EGTA alone (lane
6) during this initial phase of NF-B induction. In contrast,
when ts-abl cells were incubated at 39.5°C for 6 or 24 h to
maintain constitutive NF-B activity before treatment with
cycloheximide, the proteasome inhibitor MG132 failed to block IB
degradation (Fig. 4B, upper panel, lane 3). Similarly,
lactacystin and ALLN also failed to efficiently block IB
degradation (data not shown). Importantly, calcium chelators
efficiently inhibited IB degradation under these conditions (Fig. 4B, upper panel, lanes 4 and 5). The relative
inhibitory effects of the proteasome inhibitors and calcium chelators
were consistently reproducible in multiple independent experiments,
even though overall magnitude of the observed effects varied from
experiment to experiment due to differences in ts-abl cell induction at
the nonpermissive temperature. Thus, our findings indicate that a
nonproteasome mechanism replaces degradation of IB by proteasomes
during differentiation of these pre-B cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B in B cells traverses at least two distinct stages—induction
and maintenance—which are under the control of different regulatory
mechanisms. Similar to other cell types, the initial activation of the
latent NF-B complexes in pre-B cells requires degradation of
IB by proteasomes. In contrast, the maintenance of nuclear
NF-B in mature B cells is proteasome-independent and is mediated by
calcium-dependent degradation of IB. As such, the control of
NF-B activity during B cell differentiation is a dynamic process
switching between proteasomal and nonproteasomal pathways of IB
degradation.
This dynamic model of NF-B regulation contrasts with previously
proposed mechanisms of constitutive NF-B activity in multiple B cell
systems. Based on correlative observations, constitutive activation of
an IB kinase in Namalwa cells (20) and production of
hypophosphorylated IBß in WEHI231 cells (21) were
suggested to contribute to constitutive NF-B activity.
Phosphorylation-dependent mobility shift of IB in Namalwa cells
may be due to chronic infection by EBV, whose encoded latent membrane
protein 1 has been shown to stimulate the IB kinase (IKK) activity
(22). The latter mechanism implicated in WEHI231 cells is
identical to what was proposed for persistent activation in 70Z/3 pre-B
cells caused by chronic LPS stimulation (23). We found
that maintenance of persistent NF-B activity after LPS stimulation
requires continual proteasome-dependent degradation of IB (S.
Miyamoto, unpublished observations). Thus, this situation is distinct
from that seen in primary and transformed B cells (Figs. 1, 3, and 4).
A third proposed mechanism of constitutive NF-B activation involves
the formation of IB- or IBß-resistant RelB complexes
(24, 25, 26). Although RelB is frequently seen in NF-B
complexes at later stages of B cell maturation (activated B cells and
plasma cells) (5, 24, 25, 27, 28, 29), it is often low or
undetectable during the pre-B to immature B cell transition
(4, 5, 6). Thus, this mechanism is unlikely to explain
constitutive NF-B activation at early developmental stages which
involves primarily p50, c-Rel, and RelA subunits. Continuous
degradation of IB and/or IBß via the proteasome pathway was
also proposed to regulate NF-B activity in WEHI231 (30)
and Namalwa cells (26). However, more importantly, we
found that multiple potent proteasome inhibitors do not alter the
levels of constitutive NF-B activity in primary B lymphocytes. The
lack of inhibition of NF-B activity by proteasome inhibitors in
WEHI231 cells was also independently reported (21).
Finally, reduced IBß expression was implicated in constitutive
NF-B activation containing p50 and RelA (26). We were
unable to observe a general correlation between the levels of IBß
and constitutive NF-B activity in both primary and transformed B
cells (B. Seufzer and S. Miyamoto, unpublished observations). Thus, the
switch in the regulation of IB degradation observed in the
present study appears to involve an unprecedented model of constitutive
NF-B regulation.
Our finding that IB degradation mechanisms are dynamic when
establishing a long-term NF-B activity has several important
implications. First, existence of two distinct IB degradation
mechanisms strongly suggests that the in vivo signals responsible for
the initial induction of NF-B in pre-B cells and the maintenance of
nuclear NF-B in mature B cells may be different. The developmental
microenvironment of bone marrow pre-B cells is characterized by the
secretion of numerous cytokines and direct cell-cell contacts that are
critical for their survival and differentiation (31, 32).
Some of these components likely provide signals necessary for
proteasome-dependent induction of NF-B in pre-B cells. Newly emerged
immature B cells then leave bone marrow and migrate to the periphery.
Because constitutive NF-B activity contributes to the survival and
proliferative capacity of peripheral B cells (12, 13, 33),
an additional signal must maintain nuclear NF-B function. In light
of our results, mature B cells in the periphery likely utilize a
distinct signaling pathway that ultimately causes IB degradation
in a proteasome-independent fashion. B cell receptor signaling may
contribute to the regulation of constitutive NF-B activity, because
conditional ablation of surface Igµ on mature B cells leads to their
rapid death (34).
Second, the biochemical pathways of IB degradation in vivo are
not limited to those mediated by 26S proteasomes. Indeed, an emerging
evidence suggests that the calcium-dependent protease calpain can cause
IB degradation to regulate inducible or constitutive NF-B
activity (35, 36, 37). Calpain 3 deficiency that is
responsible for limb-girdle muscular dystrophy type 2A leads to
impaired IB proteolysis, the loss of constitutive NF-B
activity, and increased myonuclear apoptosis (37).
Although an involvement for calpain in the mechanisms that maintain
nuclear NF-B in mature B cells has not been established, a recent
definition of the molecular determinants of IB that are required
for in vitro proteolysis by calpain (38) would help to
directly test this hypothesis.
Finally, our findings suggest that NF-B regulation may be more
flexible than currently perceived. Although it is essential for the
initial induction of the latent NF-B complexes, the proteasome
pathway of IB degradation may not be required for a long-term
maintenance of nuclear NF-B activity under certain physiological or
pathological conditions. In this regard, chronic NF-B activity is
suggested to play a major role in the pathogenesis of human diseases,
including autoimmune and inflammatory disorders (39, 40),
neurodegenerative diseases (41, 42) and certain forms of
cancer (43, 44, 45). Therefore, a switch in IB
degradation pathways described in this report may not be limited only
to the B cell developmental program but may also have an impact on
certain pathogenic processes.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shigeki Miyamoto, Department of Pharmacology, University of Wisconsin Medical School, K4/554 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.
3 Abbreviations used in this paper: ts-abl, temperature-sensitive v-Abl oncoprotein; ALLN, N-acetyl-leucinyl-leucinyl-norleucinal; BAPTA-AM, 1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester; Ig-B, Ig intronic B.
Received for publication November 16, 1999. Accepted for publication February 24, 2000.
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