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B Expression and Binding to the IL-12 p40 Promoter1
Arthritis Section, Department of Medicine, Boston University Medical Center, Boston MA 02118
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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) cytokine production
characterize many autoimmune-prone mouse strains. Aberrant levels of
IL-12, for example, are produced by M isolated from young mice prone
to lupus (MRL and NZB/W) and diabetes (nonobese diabetic (NOD)) well
before the appearance of disease signs. Evaluation of the possible
mechanism(s) underlying the abnormal regulation of IL-12 in these
strains revealed novel patterns of Rel family protein binding to the
unique p40 NF-
B site in the IL-12 p40 promoter, whereas binding
patterns to Ets and CCAAT enhancer binding protein/
sites
were normal. In particular, the heightened production of IL-12 by NOD
M is associated with elevated levels of the
trans-activating p50/c-Rel (p65) complex compared with
the nonfunctional p50/p50 dimer. Conversely, the dramatically impaired
production of IL-12 by both NZB/W and MRL/+ M is associated with a
predominance of p50/p50 and reduced p50/c-Rel(p65) binding.
Mechanistically, the unique pattern seen in the lupus strains reflects
elevated p50 and reduced c-Rel nuclear protein levels. In NOD extracts,
the level of c-Rel is elevated compared with that in lupus strains, but
not when compared with that in normal A/J. However, the extent of c-Rel
tyrosine phosphorylation noted in NOD extracts is more than double that
seen in any other strain. Levels of p65 were similar in all strains
tested. These findings reveal that a common mechanism, involving
dysregulation of c-Rel and p50, may be used to determine the aberrant
IL-12 levels that have the potential to predispose specific mouse
strains to systemic or organ-specific
autoimmunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)3 from several
autoimmune-prone mouse strains are characterized by intrinsic defects
in cytokine production (3, 4, 5, 6, 7, 8, 9). These defects can be
elicited ex vivo before the onset of disease signs, and the intrinsic
nature of some of the cytokine defects has been established
(10). Of particular note, M from the NZB/W and MRL/+
lupus-prone strains produce exceedingly low levels of IL-12, whereas
M from the nonobese diabetic (NOD) and SJL strains prone to
organ-specific autoimmunity produce uniquely high levels. In the latter
group, the defects in IL-12 correlate with levels of expression of the
p40, rather than the p35, subunit of the IL-12 heterodimer (7, 8).
Such intrinsic defects in the regulation of IL-12 may prove
particularly valuable in understanding the development of autoimmunity.
IL-12 plays a critical role in the selection and maintenance of the Th1
subset (1), which, in turn, is required for eliciting
organ-specific autoimmunity (11). Moreover, IL-12 has been
shown to inhibit B cell function (12, 13), suggesting that
the reduced production of this cytokine in the MRL/+ and NZB/W strains
could contribute to lupus as well. In the current study we have
addressed the possible mechanisms underlying IL-12 dysregulation. The
evaluation of M NF binding by EMSA revealed that in all strains
tested the p40 B site binds p50 and c-Rel, with lesser involvement
of p65. Nuclear extracts from normal M express ostensibly similar
levels of DNA-binding p50/c-Rel(p65) and p50/p50 complexes. In
contrast, in NOD M, binding of the p50/c-Rel(p65)
trans-activating complex is clearly dominant and reflects an
increased fraction and total amount of tyrosine-phosphorylated (p-Tyr)
c-Rel. Strikingly, this pattern is the reverse of that seen in MRL/+
and NZB/W M, which both show a marked elevation in binding of the
inhibitory p50 homodimer. The latter pattern accurately reflects
nuclear levels of c-Rel and p50 proteins in M from these strains.
Comparison of M from six strains revealed a rigorous correlation
between the pattern of B binding and IL-12 production. These
findings suggest that a common mechanism, perturbed B/Rel binding,
may be used to direct the aberrant IL-12 levels that have the potential
to predispose individuals to systemic or organ-specific
autoimmunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five-week-old male mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were housed on-site for an additional week before use.
M isolation and culture
M were obtained from peritoneal exudate cells (PEC) by
peritoneal lavage with cold RPMI 1640 medium supplemented with 5% FBS,
1% L-glutamine, 0.5% HEPES, and 1%
penicillin/streptomycin (BioWhittaker, Walkersville, MD) 4 days after
i.p. injection of thioglycolate (2 ml; Remel, Lenexa, KS). M were
seeded either at 1.5 x 105 cells in 100
µl medium/well of 96-well plates for cytokine production (assessed by
ELISA) or at 107 cells in 10 ml
medium/100-mm-diameter dish for cytokine RNA measurements (using RNase
protection assay (RPA)) or NF (assessed by EMSA). PEC were allowed to
adhere 3 h at 37°C in 5% CO2. Nonadherent
cells were removed by washing in medium to provide cultures routinely
comprising 
95% adherent M. M were activated with 100 ng/ml
LPS, as indicated below.
ELISA
M were activated with LPS for 16 h, and conditioned
medium was collected to assess IL-12. IL-12 heterodimer (p70) and IL-12
p40 subunit levels were quantitated by OptEIA mouse IL-12
(mIL-12) p70 (catalog no. 2661KI) and mIL-12 p40 (catalog no. 2619KI)
ELISA kits (BD PharMingen, San Diego, CA), following the
manufacturer’s instructions.
RNase protection assay
M were activated with LPS for 0, 4, or 8 h, at which
time total RNA was extracted using TRIzol reagent (Life Technologies,
Gaithersburg, MD). Ten micrograms of total RNA was assessed using a
multiprobe RPA kit with the cytokine/chemokine template set mCK-2b (BD
PharMingen), following the manufacturer’s directions (catalog no.
556850).
EMSA
Nuclear extracts were prepared as described previously
(14). Sequences of EMSA oligonucleotide probes are
displayed in the legends of Figs. 2
and 3. Probes were made by
annealing single-strand oligonucleotides (Life Technologies) with
5'-GATC overhangs and were labeled by filling in with
[
-32P]dATP (NEN Life Science Products,
Boston, MA) using Klenow enzyme. The binding reaction mixture contained
10,000 cpm labeled probe, 3 µg nuclear protein, 10 mM Tris (pH 7.5),
50 mM NaCl, 1 mM EDTA, 1 mM dithiothreitol, 2 µg poly(dI-dC)
(Amersham Pharmacia Biotech, Piscataway, NJ), and 10% glycerol in a
final volume of 20 µl. The mixture was incubated for 30 min at room
temperature, and complexes were separated by PAGE (nondenaturing gel,
6% in 1x Tris-glycine-EDTA, pH 8.3) at 4°C for 1.5 h at 300 V.
The gel was dried and visualized by autoradiography. For the
competition analyses, a 100-fold molar excess of competitors was
incubated with the nuclear extracts (20 min at room temperature) before
addition of the labeled probe. For the supershift assays 2 µg of the
appropriate Abs (Santa Cruz Biotechnology, Santa Cruz, CA; see below)
were added to the reaction mixtures (30 min at room temperature) before
addition of the labeled probe.
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Nuclear extracts (16 µg) were fractionated on 7.5% SDS-polyacrylamide gels. The separated proteins were transferred to a Trans-Blot transfer membrane (catalog no. 162-0145, Bio-Rad, Hercules, CA), which was then probed by an anti-actin polyclonal Ab (catalog no. sc-1615). HRP-conjugated secondary Abs (catalog no. sc-2352 and sc-2054) were detected using chemiluminescence luminol reagent (catalog no. sc-2048). The membrane was stripped and probed, in turn, by c-Rel, p50, and p65 polyclonal Abs (catalog no. sc-71x, sc-114x, and sc-372x, respectively). Anti-phosphotyrosine Ab (catalog no. 05–321) was purchased from Upstate Biotechnology (Lake Placid, NY) and all Abs and reagents were purchased from Santa Cruz Biotechnology, except as indicated. For immunoblotting after immunoprecipitation, 16 µg of nuclear extracts were immunoprecipitated with the c-Rel Ab, and then fractionated by PAGE. Proteins thus separated were immunoblotted with the anti-phosphotyrosine Ab. To control for loading, the same membrane was then stripped and probed with the c-Rel Ab.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We had shown earlier that both NZB/W and MRL/+ M show a
striking deficiency of IL-12 p40 and p70 production compared with M
from the normal A/J strain (7), and that NOD M produce
substantially higher levels than normal (9). These studies
had compared the autoimmune-prone strains to an extensive panel of
normal strains, verifying both the relatively consistent behavior of
M from the normal strains and the polarized behavior of M from
the lupus strains compared with NOD. We had established that for NOD
M, heightened IL-12 levels were associated with correspondingly
elevated p40, but not p35, mRNA (9). The data shown in
Fig. 1, A and B,
confirm this observation and demonstrate the novel finding that the
reduced IL-12 levels noted in both NZB/W and MRL/+ M
(7) (see also Fig. 4A) are associated with correspondingly
reduced p40 mRNA.
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B binding patterns distinguish A/J, NOD, and
NZB/W M
Based on these results, nuclear extracts from LPS-activated M
were tested by EMSA for binding to sites known to be important in
regulation of IL-12 p40 transcription (15, 16, 17). The goal
was to determine whether specific patterns of NF binding might
correlate with the dysregulated expression of p40 mRNA seen in the M
from autoimmune-prone strains. The data in Fig. 2
A reveal unique patterns of
B binding in extracts prepared 2 h after M activation. The
supershift data in Fig. 2, B (A/J), C (NOD), and
D (NZB/W), reveal that binding to the B site in the p40
promoter is composed predominantly of p50 and c-Rel. Lesser amounts of
p65 also bind to this site, so we have referred to this complex as
p50/c-Rel (p65). The efficacy of the p65 Ab was demonstrated by its
successful supershifting of T cell-derived nuclear proteins bound to
the Fas ligand promoter B site (data not presented). A/J M (Fig. 2) display ostensibly similar levels of p50/p50 and p50/c-Rel(p65)
binding to the p40 B sequence. Strikingly, NF from M of the
autoimmune-prone strains differ from normal M NF in a highly
reproducible and functionally relevant manner. NOD M, which display
elevated p40 production, have a binding profile favoring the functional
heterodimer. Conversely, NZB/W M, with reduced p40 production, have
an abundance of the inhibitory p50 homodimer. Thus, it is the unique
ratio of B complexes, rather than generic hypo- or hyperexpression
of NF-B or use of distinct Rel proteins, that appears to distinguish
M from the different disease-prone strains. Similar results were
noted at 0.5 and 1 h (data not presented), suggesting that these
unique patterns are intrinsic to the M and do not result from
autocrine regulation, and that they are stable rather than
transient.
To assess the specificity of this expression pattern, other NF known to
regulate p40 transcription (16, 17) were also evaluated.
Because these NF (CCAAT enhancer binding protein (C/EBP)
and Ets) are late acting (16, 17), they were routinely
assessed at the time of optimal expression (8 and 16 h). The
results reveal binding of M NF to the C/EBP (Fig. 3A) and Ets (Fig. 3B) consensus sequences that is indistinguishable among the
three strains. The pattern of binding to both probes was also similar
among the strains at earlier time points (1 and 2 h), although the
level of binding was low (data not presented). Thus, to the extent
examined, the unique NF binding patterns that distinguish A/J, NOD, and
NZB/W M appear to be specific for the NF-B site.
Balanced homo- and heterodimer binding activity characterizes M
from normal, but not autoimmune-prone, strains
We next compared M from several normal strains to
determine whether they display a consistent pattern of NF binding to
the p40 B site, characterized by ostensibly similar levels of
p50/c-Rel(p65) and p50/p50. We also evaluated MRL/+ M to determine
whether there was evidence for a consensus pattern among lupus-prone
strains. As shown in Fig. 4A,
each of the three normal strains tested (A/J, B/6, and BALB/c) produced
very similar levels of IL-12 p40 and p70 proteins. This is in striking
contrast to production of the cytokines TNF and IL-10, which varies by
over 20-fold among these strains (6). Thus, regulation of
IL-12 production is unusual in that it is normally held within rigid
limits. Clearly, M from autoimmune-prone strains are aberrant in
IL-12 production: NOD M produce heightened p70 and p40 levels (410
and 350% of the mean normal values, respectively), whereas M from
both lupus strains produced low levels (NZB/W, 24 and 49%; MRL/+, 11
and 25% of the mean normal p70 and p40 levels, respectively).
Evaluation by EMSA (Fig. 4B) demonstrated similar
binding of the two dominant Rel complexes in M NF obtained from each
normal strain, and these findings were quantitated by densitometry in
Fig. 4C. Thus, this pattern is consistent with the conserved
levels of IL-12 production seen in normal strains (Fig. 4A)
(7, 8, 9). Additionally, the data reveal that the
IL-12-deficient M from the MRL/+ strain, which displays late-onset
lupus independent of the lpr mutation, share the same B
perturbation (dominance of p50/p50 binding) seen in NZB/W M. Taken
together, these "experiments of nature" suggest that divergence
from the normal balance of B binding leads to the aberrant IL-12
levels that characterize each of the autoimmune-prone strains tested.
This interpretation is supported by the regression analysis seen in
Fig. 4D; there is a virtually absolute correlation of the
B binding pattern (ratio of hetero- to homodimer) and the amount of
p40 and p70 proteins produced.
Additional findings (our unpublished observations) further
support this view. First, M from the NOD-congenic, but
diabetes-resistant, NOR strain, which produce normal levels
of IL-12 (9), express the normal balance of hetero- and
homodimer. This reveals that in the NOR, a strain of near genetic
identity to the NOD, there is conserved 1) genetic resistance to
disease, 2) normal M IL-12 production, and 3) normal Rel family
binding to the p40 B site. Second, we have found that the defect in
NZB/W M IL-12 production is derived from the NZW, not the NZB,
parent (D. Alleva and D. Beller, unpublished observations). Preliminary
findings indicate that the prevalence of p50 homodimer binding seen the
NZB/W is likewise associated with the NZW parent. Taken together, these
findings suggest a common mechanism underlying the bias toward
dysregulated M IL-12 production characteristic of
autoimmune-prone mice.
Levels of nuclear p50 and c-Rel in NZB/W and MRL/+, but not in NOD, reflect their DNA binding activity
In an effort to determine the basis for the unique patterns of
B binding in the different strains, nuclear extracts were
fractionated by SDS-PAGE, and proteins were identified by
immunoblotting (Fig. 5A). The
results reveal that for both lupus strains (NZB/W and MRL/+), nuclear
c-Rel levels are reduced, while p50 is increased, relative to those in
A/J mice. The pattern in NOD, by contrast, appears similar to that in
A/J. The relative levels of p50, c-Rel, and p65 were then determined by
densitometry, adjusted for actin levels in each extract, and normalized
to the adjusted A/J Rel level, arbitrarily set at 1 (Fig. 5B). The relative levels of p65 served as an internal
control, being nearly identical in all strains; p65 expression
normalized to A/J was 0.99, 0.91, and 1.05 for NZB/W, MRL/+, and NOD,
respectively. The extent of reduction in the ratio of c-Rel to p50
protein in M nuclear extracts from the lupus-prone strains compared
with that in normal mice is consistent with the reduction in each of
the following: 1) p50/c-Rel(p65):p50/p50 binding to the p40 B
site (EMSA), 2) the level of p40 mRNA (RPA), and 3) p40 and p70 protein
levels (ELISA). Thus, the ratio of c-Rel to p50 may be sufficient to
explain the reduced activity of the p40 promoter in these two
lupus-prone strains. This is not the case in extracts from NOD M,
where both the relative level of nuclear Rel proteins and the ratio of
c-Rel to p50 are indistinguishable from those in A/J. This suggests
that in the NOD M a factor other than the level of nuclear Rel
protein determines the specific pattern of Rel binding to the B
site.
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Phosphorylation is one means by which the function of c-Rel is
post-translationally regulated (18). To test the
possibility that phosphorylation of nuclear c-Rel is elevated in NOD
M, nuclear proteins were immunoprecipitated with anti-c-Rel Ab,
separated by PAGE, and then immunoblotted with anti-phospho-tyr Ab.
The same membrane was stripped and immunoblotted with c-Rel to
determine relative c-Rel levels. As shown in Fig. 6A, A/J and NOD nuclear
extracts contained similar levels of c-Rel, which were higher than
c-Rel expression in lupus strains. However, tyr-phosphorylated c-Rel
(p-Tyr c-Rel) was elevated in the NOD, both in absolute level and as a
fraction of the total c-Rel. The results were then quantitated by
densitometry (Fig. 6B) and normalized to the levels found in
A/J (each was arbitrarily assigned a value of 1 for A/J) to more
accurately determine the relative expression among strains. The
fraction of c-Rel that is tyr-phosphorylated is 
2.5 times greater in
NOD than in normal or lupus strains. The amount of p-Tyr c-Rel in NOD
was nearly 3 times that in A/J, 6 times that in NZB/W, and 12 times the
level in MRL (based on equivalent protein loading). Thus,
phosphorylation of c-Rel may be critical in determining the unique B
binding patterns seen in NOD M.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B/Rel family members. Intrinsic defects in the
regulation of IL-12 may prove particularly valuable in understanding
the development of autoimmunity. To our knowledge, dysregulation of
IL-12 is the only protein-specific, intrinsic defect displayed in a
wide range of autoimmune-prone mouse models (7, 8, 9). IL-12
plays a critical role in the selection and maintenance of the Th1
subset required for eliciting organ-specific autoimmune disease
(11). For example, IL-12 blockade has been shown to
inhibit the development of diabetes in the NOD mouse (19).
Of note, depletion of M also blocks the development of NOD disease;
diabetes is reinstated in the M-depleted NOD mouse by administering
IL-12 (20), suggesting that the production of this
cytokine by M is a key event in the pathogenesis of NOD disease.
Thus, the specific control of IL-12 production may be important in
explaining the basic dichotomy of organ-specific and system autoimmune
diseases. The potential for overexpression of IL-12 may predispose
diabetes-prone mice toward a Th1-mediated pathway of organ-specific
autoimmunity, while reduced IL-12 in lupus-prone mice would be expected
to promote B cell-mediated systemic autoimmunity. Recent reports that
IL-12 inhibits B cell function in a more proximal fashion (12, 13) suggest additional mechanisms by which the deficiencies in
IL-12 production in NZB/W and MRL/+ mice may contribute to B cell
hyperactivity and autoantibody production. We have indeed found that
coculture of B cells with M or dendritic cells from NZB/W or MRL/+
mice leads to augmented IgM production compared with coculture with APC
from several normal strains (D. Alleva, J. Liu, T. Jones, and D.
Beller, unpublished observations) and are currently exploring
the mechanism involved.
Recently, NF-B defects (specifically, reduced levels of p65) have
been reported in T cells from lupus patients (21).
Additionally, it has been shown that NOD dendritic cells overexpress
B/Rel as a consequence of enhanced function of IB kinase
(22). In distinction to our findings, the latter group
reported an increase in both hetero- and homodimer binding using a
consensus MHC I NF-B sequence rather than a specific IL-12 p40 B
sequence as used here. We have found that, indeed, the hetero- and
homodimers bind to a Bc site (TNF-2) with a ratio of 1 in A/J,
NOD, and NZB/W (data not presented), suggesting that the pattern of
enhanced homo- and heterodimer binding noted in the study of dendritic
cells (22) is likely to reflect the B sequence chosen,
although a contribution of the cell type studied cannot be ruled out at
this time. Sanjabi et al. (23) reported that while c-Rel,
but not p65, was critical for regulation of M p40 expression, both
Rel proteins bound the p40 B oligo with similar affinity. This would
appear to be at odds with our finding of preferential binding of c-Rel
to this site. However, Sanjabi et al. (23) stimulated M
with both LPS and IFN-
, while we used LPS alone. The difference in
our findings may be explained by the report by Brown et al.
(24), which showed that LPS stimulation of M induced a
B-binding heterodimer comprised predominantly of c-Rel, whereas
stimulation with both LPS and IFN- led to a heterodimer comprised of
similar levels of c-Rel and p65. Taken together, these findings suggest
that the precise composition of the heterodimer may be regulated by the
stimulus encountered by the M. Additionally, it has been shown that
1) mutation of the 5' region of the B site leads to a shift in
binding preference from p50/p65 to p50/c-Rel (25), and 2)
mutated c-Rel proteins display unique affinities for different native
B sites (26). Thus, subtle differences in the B site
or in flanking sequences in different promoters may also contribute to
the composition of the B/Rel heterodimer that binds this sequence.
The functional importance of our findings is supported by 1) the
extraordinary correlation of the B/Rel binding pattern with IL-12
production among a wide range of strains, 2) the documented importance
of c-Rel (rather than p65) in NF-B binding to the M p40 B site
and in the selective activation of M p40 transcription (15, 16, 23), and 3) the known inhibitory function of the p50
homodimer (27). The finding of a conserved expression of
NF-B defects in autoimmunity also may provide insight into the
shared genetic loci associated with lupus, diabetes, arthritis, and
experimental autoimmune encephalomyelitis (28). To
our knowledge this is the first report linking selective binding of
proteins from complex NF families with animal models displaying
selective induction of systemic vs organ-specific autoimmunity. These
findings also demonstrate the near identity in molecular regulation of
M IL-12 expression in two distinct lupus models (MRL/+ and NZB/W),
showing strikingly similar levels of 1) IL-12 p40 and p70 protein, 2)
p40 mRNA, 3) hetero- vs homodimer binding to the p40 B site, and 4)
the ratio of nuclear c-Rel to p50. At the same time, immunoblot results
provide the first evidence for unique mechanisms of regulation of the
IL-12 defects among autoimmune-prone strains, revealing that, unlike
the lupus strains, NOD M cannot rely solely on nuclear Rel levels to
direct the hetero- and homodimer DNA binding anomaly. Enhanced
phosphorylation of nuclear c-Rel may be one means by which elevated
c-Rel binding occurs in NOD M. Phosphorylation regulates NF-B
activity both indirectly, via IB degradation and release of NF-B,
and directly, through modulation of the Rel homology domain, leading to
acquisition of trans-activating function. However, another
mechanism for direct regulation of Rel family proteins and for c-Rel in
particular, is phosphorylation-mediated enhancement of DNA binding
function (18). c-Rel is phosphorylated after activation
(29), and nonphosphorylated c-Rel does not bind to the
B site (30).
Thus, determination of the mechanisms by which 1) p50 is preferentially
elevated in the cytosol or translocated to the nucleus in NZB/W and MRL
M, and 2) c-Rel is more actively phosphorylated in NOD M is
likely to reveal the molecular basis for inherent defects in IL-12
regulation in these strains. Taken together, these data strongly
suggest that the balance of hetero- and homodimer bound to the B
site contributes to, and may determine, the level of p40 and functional
IL-12 p70 production in these mouse strains. Defining the mechanisms
responsible for these unique NF patterns should reveal novel molecular
targets relevant to several autoimmune diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David Beller, Arthritis Section, Evans 5, Department of Medicine and Evans Department of Clinical Research, Boston University Medical Center, 715 Albany Street, Boston, MA 02118. E-mail address: dbeller{at}medicine.bu.edu
3 Abbreviations used in this paper: M, macrophage; c, consensus (sequence); mIL-12, mouse IL-12; PEC, peritoneal exudate cell; p-Tyr c-Rel, tyrosine-phosphorylated c-Rel; RPA, RNase protection assay; C/EBP, CCAAT enhancer binding protein .
Received for publication February 21, 2002. Accepted for publication April 29, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in murine autoimmune lupus nephritis. Nature 331:356.[Medline]
+ T cells. J. Immunol. 161:1483.B half-site. Mol. Cell. Biol. 15:5258.[Abstract]
B by direct phosphorylation. J. Biol. Chem. 268:26790. cell destruction. VI. Macrophages are essential for the development of cell-specific cytotoxic effectors and insulitis in NOD mice. Diabetes 39:1273.[Abstract]
B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J. Immunol. 163:1682.B regulation due to a hyperactive IB kinase. J. Immunol. 167:1461.B1 (p105/p50) in murine macrophages: differential regulation by lipopolysaccharide, interleukin-2, and interferon-. J. Interferon Cytokine Res. 17:295.[Medline]
B/Sp1 region is essential for chromatin remodeling and correct transcription of a human granulocyte-macrophage colony-stimulating factor transgene. J. Immunol. 167:302.B DNA-binding properties of v-Rel and c-Rel are the result of oncogenic mutations in three distinct functional regions of the Rel protein. Oncogene 14:2881.[Medline]
transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-B p50. Mol. Cell. Biol. 18:5678.B. Oncogene 7:2095.[Medline]
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U. Grohmann, F. Fallarino, R. Bianchi, C. Orabona, C. Vacca, M. C. Fioretti, and P. Puccetti A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice J. Exp. Med., July 7, 2003; 198(1): 153 - 160. [Abstract] [Full Text] [PDF]
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J. Liu and D. I. Beller Distinct Pathways for NF-{kappa}B Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains J. Immunol., May 1, 2003; 170(9): 4489 - 4496. [Abstract] [Full Text] [PDF]
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P. K. Potter, J. Cortes-Hernandez, P. Quartier, M. Botto, and M. J. Walport Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells J. Immunol., March 15, 2003; 170(6): 3223 - 3232. [Abstract] [Full Text] [PDF]
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P. Sen, S. Bhattacharyya, M. Wallet, C. P. Wong, B. Poligone, M. Sen, A. S. Baldwin Jr., and R. Tisch NF-{kappa}B Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages J. Immunol., February 15, 2003; 170(4): 1770 - 1780. [Abstract] [Full Text] [PDF]
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F. Bouzahzah, S. Jung, and J. Craft CD4+ T Cells from Lupus-Prone Mice Avoid Antigen-Specific Tolerance Induction In Vivo J. Immunol., January 15, 2003; 170(2): 741 - 748. [Abstract] [Full Text] [PDF]
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