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B- Deficient Mice: Roles of NF-B in the Activation and Differentiation of Autoreactive T Cells1
*
Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, and
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B family, which is present in a variety of cell
types and becomes highly activated at sites of inflammation. To test
the roles of NF-B in the development of autoimmune diseases, we
studied EAE in mice deficient in one of the NF-B isoforms, i.e.,
NF-B1 (p50). We found that NF-B1-deficient mice were
significantly resistant to EAE induced by myelin oligodendrocyte
glycoprotein. The resistance was primarily evidenced by a decrease in
disease incidence, clinical score, and the degree of CNS inflammation.
Furthermore, we established that the resistance to EAE in
NF-B1-deficient mice was associated with a deficiency of myelin
oligodendrocyte glycoprotein-specific T cells to differentiate into
either Th1- or Th2-type effector cells in vivo. These results strongly
suggest that NF-B1 plays crucial roles in the activation and
differentiation of autoreactive T cells in vivo and that blocking
NF-B function can be an effective means to prevent autoimmune
encephalomyelitis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Development of autoimmune diseases requires coordinated expression of a number of immune-related genes. These include genes that encode costimulatory molecules, Ag receptors, cytokines, chemokines, adhesion molecules, and cytotoxic enzymes. These molecules play crucial roles in the activation, migration, and the effector functions of inflammatory cells. The outcomes of autoimmune diseases are largely dictated by the relative contributions of these molecules. To date, little is known about the molecular events leading to the expression of these immune-related genes in autoimmune diseases, although a combination of genetic and environmental factors has been implicated. Elucidation of the molecular mechanisms whereby expression of these genes is regulated is essential for our understanding the pathogenesis of autoimmune diseases.
Expression of immune-related genes is regulated by several families of
transcription factors including NF-B/Rel family, AP-1, and NF-IL-6.
The NF-B/Rel family consists of at least five members: NF-B1
(p50/p105), NF-B2 (p52/p100), RelA (p65), RelB, and c-Rel
(1, 2, 3, 4). Although initially identified as a transcription
factor for the light-chain gene in murine B cells, NF-B is
constitutively expressed in a variety of cell types, including
lymphocytes, monocytes/macrophages, and granulocytes, as well as cells
of nonimmune systems (1, 2, 3, 5, 6, 7). It is located primarily
in the cytoplasm as an inactive homo- or heterodimeric protein in
association with the inhibitory protein called IB. There are at
least seven IBs that all act by masking the nuclear localization
signal of NF-B, preventing its nuclear translocation. A wide variety
of stimuli, including cytokines, Ags, stress factors, and viral and
bacterial products can activate NF-B (1, 2, 3, 4, 8).
Activation of NF-B involves phosphorylation and proteolytic
degradation of the inhibitory protein IB by specific IB kinases.
The free NF-B then passes into the nucleus, where it binds to the
B sites of gene promoters. Many immune-related genes contain the
B binding sites in their promoter regions, and may, therefore, be
activated by NF-B. These include genes that encode costimulatory
molecules, MHC molecules, cytokines (such as TNF-
, IL-1ß, IL-2,
IL-6, GM-CSF), chemokines (such as IL-8, macrophage-inflammatory
protein-1, macrophage-chemotactic protein-1, and eotaxin),
inflammatory enzymes (such as inducible nitric oxide synthase,
inducible cyclooxygenase, 5-lipoxygenase, and phospholipase-A2), and
adhesion molecules (such as ICAM-1, VCAM-1, and E-selectin)
(1, 2, 3, 4, 9, 10, 11, 12).
Recent studies in NF-B-deficient mice suggest that different forms
of NF-B may be endowed with different functions. Thus, mice
deficient in NF-B1 (p50/p105) develop normally and acquire a
structurally normal immune system. However, they are more susceptible
to intracellular and extracellular Gram-positive bacterial infections,
and are partially compromised in their B cell responses to LPS
(3). Surprisingly, they are resistant to viral and
Gram-negative bacterial infections (3). By contrast, mice
deficient in NF-B2 suffer from severe developmental defects. Both
their spleens and lymph nodes are bereft of B lymphocytes, undermining
their capacity to form germinal centers (13, 14). Not
surprisingly, NF-B1/NF-B2 double-deficient mice suffer from both
developmental and immunological abnormalities. RelA-deficient mice die
in utero, presumably due to enhanced hepatocyte apoptosis (2, 15). Both RelB- and c-Rel-deficient mice develop normally, but
suffer from severe disorders ranging from splenomegaly to chronic
microbial infections (16, 17). These studies strongly
suggest that members of the NF-B/Rel family perform nonoverlapping
functions, and that loss of function mutations of NF-B/Rel genes
cannot be compensated by other members of the NF-B/Rel family.
To determine the roles of NF-B in the development of autoimmune
diseases, we studied experimental autoimmune encephalomyelitis
(EAE)4 in
NF-B1-deficient B6.129 mice. As NF-B1-deficient mice do not
suffer from developmental abnormalities, the differences in EAE between
these mice and their littermate controls can be solely attributed to
NF-B1. Our results strongly suggest that NF-B1 plays crucial
roles in the activation and differentiation of myelin oligodendrocyte
glycoprotein (MOG)-specific T cells in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four- to six-week-old (B6 x 129)F2
(B6.129) mice homozygous for NF-B1 mutation and their littermate
controls were purchased from The Jackson Laboratory (Bar Harbor, ME),
and were housed in the University of Pennsylvania Animal Care
Facilities (Philadelphia, PA). The NF-B1 gene mutation was created
by inserting the neor cassette into the
sixth exon of the NF-B1 gene (13). Mice were screened
for NF-B1 gene mutation by RT-PCR and Southern blot analysis
(13).
Induction and clinical evaluation of EAE
For the induction of EAE, mice received 1) a s.c. injection on flanks of 200 µg MOG38–50 peptide in 0.1 ml PBS emulsified in an equal volume of CFA containing 4 mg/ml of Mycobacterium tuberculosis H37RA (Difco, St. Louis, MO), and 2) an i.v. or i.p. injection of 200 ng pertussis toxin in 0.1 ml PBS. A second injection of pertussis toxin (200 ng per mouse) was given 24 or 48 h later. Mice were examined daily for signs of EAE and scored as follows (18, 19): 0, no disease; 1, tail paralysis; 2, hind limb weakness; 3, hind limb paralysis; 4, hind limb plus forelimb paralysis; 5, moribund or dead.
Ags, Abs, recombinant cytokines, and ELISA
Mouse MOG38–50 peptide was synthesized
using Fmoc solid-phase methods and purified through HPLC by Research
Genetics (Huntsville, AL). Pertussis toxin was purchased from List
Biological Laboratories (Campbell, CA). The following reagents were
purchased from PharMingen (San Diego, CA): purified rat anti-mouse
IL-2, IL-4, IL-10, and IFN-
mAb; recombinant mouse IL-2, IL-4,
IL-10, and IFN-. Quantitative ELISA for IL-2, IL-4, IL-10, and
IFN- was performed using paired mAbs specific for corresponding
cytokines per manufacturer’s recommendations (20).
Cell culture
For cytokine assays, splenocytes were cultured at 1.5 x 106 cells/well in 0.2 ml of serum-free medium X-Vivo 20 (BioWhittaker, Walkersville, MD), containing various concentrations of MOG38–50 peptide, OVA, or Con A (Sigma, St. Louis, MO) (19). Culture supernatants were collected 40 h later, and cytokine concentrations were determined by ELISA. For proliferation assays, 0.75 x 10 6 cells/well were used. [3H]Thymidine was added to each culture at 72 h, and cells were harvested 16 h later. Radioactivity was determined using a flatbed beta counter (Wallac, Gaithersburg, MD).
Histology
Brains and spinal cords were harvested at the end of each experiment, fixed in 10% Formalin, and embedded in paraffin. Five-micrometer-thick paraffin sections were stained with hematoxylin and eosin (HE) or with Luxol fast blue, as described (21).
Flow cytometry
Single cell suspensions of spinal cords were prepared as follows. Mice were first anesthetized by i.p. injection of xylazine ketamine, and perfused through the left ventricle with PBS. Spinal cords were removed, placed in ice-cold RPMI medium containing 27% Percoll, and pressed through a 70-µm Falcon cell strainer (#2350; Becton Dickinson, Franklin Lakes, NJ). The resulting cell suspension was brought to a volume of 50 ml with 27% Percoll, mixed, and centrifuged at 300 x g for 15 min. The pellet was kept on ice, while the myelin layer and the supernatant were transferred to a new 50-ml tube, homogenized by shaking, and centrifuged again at 300 x g for 15 min. The pellets were then combined and washed three times in RPMI medium at 4°C.
For flow cytometry analysis, single cell suspensions of spinal cords and spleens were first incubated for 45 min with either 1) anti-mouse CD11b-FITC (clone M1/70.15), anti-mouse B220-tricolor (clone RA3-6B2), anti-mouse CD3-biotin (clone 500-A2), (Caltag Laboratories, Burlingame, CA) together with PE-labeled anti-mouse B7-2 (clone GL-1), CD45RB (clone C363.16A, also known as 16A), or CD122 (clone TM-B1) (PharMingen, San Diego, CA), or 2) anti-mouse CD3-biotin, anti-mouse B220-tricolor, and anti-mouse B7-1-FITC (clone 16-10A1; PharMingen). Cells were then washed three times, incubated with streptavidin-APC (PharMingen), and analyzed directly using a FACScan flow cytometer (Becton Dickinson Immunocytometry Systems, Mountain View, CA).
Statistical analysis
Disease severity, day of onset, and cytokine concentrations were analyzed by ANOVA. Disease scores were analyzed by Mann-Whitney test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B-deficient mice are resistant to EAE
To study the roles of NF-B in the development of EAE, we
immunized NF-B1-deficient B6.129 mice
(NF-B-/-) and their control littermates
(NF-B+/+) with MOG38–50
peptide, and monitored the disease by both physical examination and
histochemistry. Fig. 1
illustrates
typical disease courses in control and NF-B-deficient B6.129 mice.
EAE developed in most (88%) control B6.129 mice, starting 
10 days
after immunization and reaching a maximal mean clinical score of 2.6
two weeks later. The disease took a remitting-relapsing course with a
low mortality rate. By contrast, in NF-B1-deficient group, only 38%
of mice developed symptoms of EAE. The disease severity was
dramatically reduced, reaching a maximal mean disease score of only
0.8. The onset of the disease was also delayed by 6 days (Fig. 1, Table I).
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). These include cells
with morphological characteristics of lymphocytes, granulocytes,
macrophages, microglial cells, as well as astrocytes. By contrast, no
lesions were detected in the CNS of NF-B-deficient mice that showed
no symptoms of EAE. In those NF-B-deficient mice that did develop
EAE, similar inflammatory infiltrates were observed (Fig. 2). Luxol
fast blue staining was also performed to visualize demyelination in the
CNS (21); severe demyelination was noted only in mice with
disease scores above 2 (E. B. Samoilova and Y. Chen, unpublished
data). Taken together, these results strongly suggest that NF-B
plays important roles in EAE.
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B-deficient animals
Resistance to EAE in NF-B-deficient mice can be either due to
the inability of myelin-specific T cells to differentiate into effector
T cells in the periphery, or due to the inability of differentiated
effector T cells to induce demyelinating inflammation in the CNS, or
both. To address this issue, we first examined whether activation and
differentiation of myelin-specific T cells were normal in
NF-B-deficient animals. Splenocytes were, therefore, collected from
both control and NF-B-deficient mice 32 days after immunization, and
tested in vitro for their cytokine production and proliferation in
response to MOG38–50 peptide. As shown in Fig. 3, splenocytes of control animals
proliferated vigorously in response to MOG peptide and produced
significant amounts of both Th1 (IL-2 and IFN-)- and Th2 (IL-4,
IL-10)-type cytokines. By contrast, splenocytes from NF-B-deficient
animals produced significantly less amounts of these cytokines, and
proliferated poorly in response to MOG stimulation (Fig. 3). (The
relatively low degree of proliferation of Con A-stimulated cells may
relate to the time point used for [3H]thymidine
pulsing.) Interestingly, NF-B appears to have a more dramatic effect
on Th2 cytokine production. Even Con A-induced Th2 cytokine release was
affected by the NF-B deficiency, with IL-4 production being
increased while IL-10 production decreased in NF-B-deficient mice.
Further studies are required to address the potential differential
effects of NF-B on Th2 cytokines.
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B-deficient mice.
Frequencies of normal and NF-B-deficient inflammatory cells in
the CNS
Having had established a role for NF-B in the activation and
differentiation of encephalitogenic T cells, we next sought to explore
the potential roles of NF-B in the effector stage of EAE. Adoptive
transfer experiment could not be performed in B6.129
F2 mice because the F2 mice
are not 100% identical in their genetic makeup (although the
collective genetic makeup of a group of B6.129 F2
mice should be identical with that of other groups). We, therefore,
performed a series of flow-cytometric analyses of inflammatory cells
infiltrating the CNS, in an attempt to define the phenotypic and
functional characteristics of these cells in the CNS.
Large numbers of control and NF-B1-deficient B6.129
F2 mice were, therefore, immunized with MOG to
generate mice with comparable degrees of EAE. Mice were then divided
into two groups based on their disease severity: group 1, those with
mild EAE (scores 1–2), and group 2, those with severe EAE (scores
3–5). Single cell suspensions of spinal cords were then prepared from
these mice and examined by flow cytometry as in Fig. 4.
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summarizes the results of these
experiments. First, we found that the numbers of inflammatory cells
isolated in this manner correlated extremely well with the severity of
the disease (Table II). Thus, the numbers of
CD11b+, CD3+, and
B220+ cells in the spinal cord of
NF-B-deficient mice with mild EAE (scores 1–2) were 59,525, 52,500,
and 21,450, respectively. These were increased 4-fold in
NF-B-deficient mice with severe EAE (scores 3–5). A roughly
2-fold increase was observed in control B6.129 mice (Table II).
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B-deficient mice were dramatically increased as compared
with control mice with severe EAE. Specifically, the numbers of
CD11b+, CD3+, and
B220+ cells per spinal cord of control mice with
severe EAE were 90,563, 93,194, and 37,376, respectively; these were
increased by 2-fold in the NF-B-deficient mice (Table II
). As the
clinical scores of these two groups are essentially the same, this
increase in inflammatory cells in NF-B-deficient mice suggests that
NF-B may be involved in regulating migration and/or effector
functions of inflammatory cells. In this regard, it has been reported
that NF-B regulates the expression of a number of genes involved in
leukocyte extravasation (e.g., VCAM-1, ICAM-1, E-selectin, and
chemokines) and effector functions (e.g., proinflammatory cytokines,
inducible nitric oxide synthase, cyclooxygenase-2, etc.) (1, 2, 3, 4, 9, 10, 11, 12). In the absence of NF-B, expression of these genes may
be hindered, and migration/effector functions of inflammatory cells
dysregulated. Further studies are needed to prove or disprove this
theory.
It is to be noted that in mice with mild EAE (scores 1–2), no
differences in inflammatory cell frequencies were observed between
control and NF-B-deficient mice, suggesting that NF-B may not be
equally involved in the development of mild EAE. It is also to be noted
that the differences in inflammatory cell frequencies may not be due to
changes in leukocyte numbers in the periphery, because the numbers of
leukocytes in NF-B-deficient mice were either comparable with, or
slightly less than those of control mice (Table III) (3). In parallel
experiments, we have also immunized B6.129 mice with CFA and pertussis
toxin in the absence of myelin Ags; this did not lead to the
development of EAE, and no significant numbers of lymphoid/myeloid
cells could be isolated from the CNS of treated animals.
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B-deficient
cells in the CNS
To determine whether NF-B-deficient cells differ from normal
cells in their activation marker expression, we tested CD45RB, CD122,
and B7 expression by flow cytometry (Fig. 5). We found that most
CD3+ cells infiltrating CNS are
CD45RBlow, suggesting that they are activated T
cells. Although only a small percentage of these cells express high
levels of CD122, 60% of them express both B7-1 and B7-2 (Table IV). Surprisingly, no differences were
detected between control and NF-B-deficient cells (Table IV).
Similarly, CD3- cells infiltrating the CNS also
express B7 and CD45RB. Again, no differences were observed between
normal and NF-B-deficient mice (Fig. 5, Table IV). These results
suggest that NF-B deficiency may not affect B7, CD45RB, and CD122
expression in the CNS.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B, AP-1, and NF-IL-6. These factors, acting either alone or in
combination, orchestrate the initiation and/or progression of
autoimmune diseases. The transcription factor NF-B is expressed by
both the immune and nervous systems, and may, therefore, regulate
autoimmune inflammation in the CNS through different mechanisms. By
directly binding to the corresponding DNA sequence (the B site)
located in the promoter regions of target genes, NF-B expressed by
lymphocytes and cells of the innate immune system may orchestrate
autoimmune encephalomyelitis through two distinct pathways. First,
NF-B regulates the expression of both TCR and costimulatory
molecules that are required for the activation and differentiation of
myelin-specific precursor T cells (4, 22, 23, 24). Second,
NF-B regulates expression of genes required for migration
(chemokines, adhesion molecules) and effector functions of inflammatory
cells (cytokines, inflammatory enzymes) (1, 2, 3, 4, 9, 10, 11, 12, 22, 25, 26, 27, 28, 29) and induces expression of antiapoptotic proteins such as
TNF receptor-associated factor and inhibitor of apoptosis (which in
turn protect inflammatory cells from apoptosis) (30, 31, 32, 33, 34, 35, 36).
Therefore, the combined effect of NF-B action in the immune system
may be to promote formation, and to prevent resolution, of inflammatory
lesions in the CNS. By contrast, NF-B expressed in the CNS may play
opposite roles in autoimmune encephalomyelitis. By activating genes
encoding antiapoptotic proteins, NF-B expressed by neural cells may
prevent them from inflammation-induced cell death, and therefore
promote remyelination and disease recovery. Thus, the net effect of
NF-B on autoimmune inflammation is most likely determined by a
balance between these opposing actions. Studies presented in this work
seek to address this issue using a model of MOG-induced autoimmune
encephalomyelitis. To our knowledge, this is the first report examining
the roles of NF-B in EAE using transcription factor-deficient
mice.
Our results suggest that at least one member of the NF-B family,
i.e., NF-B1, plays a crucial role in the inductive phase of EAE. The
inductive phase of EAE involves primarily activation of myelin-specific
lymphocytes. In the present study, this was achieved by immunizing mice
with MOG peptide together with CFA. Although it is clear that MOG and
the adjuvant activate specific T cells through generating the first and
the second signals, the transcriptional elements involved in this
process are poorly understood. Our observation that MOG-specific T cell
activation is hindered in NF-B1-deficient mice suggests that
NF-B1 may be one of the transcriptional regulators that are
important for the initiation of the disease. In the absence of
NF-B1, autoreactive T cells may not be fully activated and may not
effectively differentiate into Th1- or Th2-type cells; therefore,
severe autoimmune encephalomyelitis may not develop even with active
immunization with myelin Ags and adjuvants.
The precise mechanisms of NF-B action in the generation of
autoreactive effector T cells need now to be investigated. As alluded
to above, NF-B may be directly involved in the TCR or costimulatory
signaling. In this regard, it has been shown that NF-B is directly
involved in T cell activation in a number of systems (12, 22, 24, 26, 37). Alternatively, NF-B may indirectly regulate T cell
activation through modulating the expression of such molecules as
cytokines, chemokines, MHC, and costimulatory and adhesion molecules,
which are required for T cell activation (1, 2, 3, 4, 9, 10, 11, 12, 23). In the absence of NF-B, these pathways may be blocked.
Experiments are underway to prove or disprove these hypotheses.
It is to be noted that our experiments do not directly address the
question whether NF-B plays a role in the effector stage of EAE.
Activation of autoreactive T cells is severely compromised in
NF-B-deficient mice, making it difficult to determine the functions
of NF-B-deficient effector cells in EAE. The B6.129
F2 mice used in this study are not 100%
identical in their genetic makeup, precluding adoptive transfer
experiments using isolated T cells. Nonetheless, our observation that
the numbers of inflammatory cells present in NF-B-deficient mice
with severe EAE were significantly higher than those in control mice
suggests that NF-B may be indeed involved in the effector stage of
EAE. In the absence of NF-B, migration and/or effector functions of
inflammatory cells may be dysregulated. In support of this theory,
Vanderlugt et al. recently showed that PS-519, a selective inhibitor of
the ubiquitin-proteasome pathway that inhibits activation of NF-B,
could down-regulate ongoing EAE (38). Administration of
PS-519 during the remission phase, following acute clinical disease,
was effective in significantly reducing the incidence of clinical
relapses, CNS histopathology, and T cell responses to both the
initiating and relapse-associated proteolipid protein epitopes
(38). Further studies are required to address these
issues.
In summary, we have discovered a critical role for NF-B in the
development of EAE. This finding may not only be important for our
understanding of the basic mechanisms of autoimmunity, but also aid in
designing novel therapeutic strategies for the treatment of autoimmune
diseases such as multiple sclerosis.
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Footnotes |
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2 B.H. and E.B.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Youhai Chen, BRB-1, Room 401, Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail address:
4 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein.
Received for publication February 18, 1999. Accepted for publication June 22, 1999.
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 M. J. Fabis, G. S. Scott, R. B. Kean, H. Koprowski, and D. C. Hooper Loss of blood-brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models PNAS, March 27, 2007; 104(13): 5656 - 5661. [Abstract] [Full Text] [PDF]
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R. J. Carmody, Q. Ruan, H.-C. Liou, and Y. H. Chen Essential Roles of c-Rel in TLR-Induced IL-23 p19 Gene Expression in Dendritic Cells J. Immunol., January 1, 2007; 178(1): 186 - 191. [Abstract] [Full Text] [PDF]
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 F.-Q. Li, G. D. Sempowski, S. E. McKenna, D. T. Laskowitz, C. A. Colton, and M. P. Vitek Apolipoprotein E-Derived Peptides Ameliorate Clinical Disability and Inflammatory Infiltrates into the Spinal Cord in a Murine Model of Multiple Sclerosis J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 956 - 965. [Abstract] [Full Text] [PDF]
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M. Pelletier and D. Girard Differential Effects of IL-15 and IL-21 in Myeloid (CD11b+) and Lymphoid (CD11b-) Bone Marrow Cells J. Immunol., July 1, 2006; 177(1): 100 - 108. [Abstract] [Full Text] [PDF]
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L. Klotz, M. Schmidt, T. Giese, M. Sastre, P. Knolle, T. Klockgether, and M. T. Heneka Proinflammatory Stimulation and Pioglitazone Treatment Regulate Peroxisome Proliferator-Activated Receptor {gamma} Levels in Peripheral Blood Mononuclear Cells from Healthy Controls and Multiple Sclerosis Patients J. Immunol., October 15, 2005; 175(8): 4948 - 4955. [Abstract] [Full Text] [PDF]
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J. Sun, B. Hilliard, L. Xu, and Y. H. Chen Essential Roles of the Fas-Associated Death Domain in Autoimmune Encephalomyelitis J. Immunol., October 1, 2005; 175(7): 4783 - 4788. [Abstract] [Full Text] [PDF]
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C. Benou, Y. Wang, J. Imitola, L. VanVlerken, C. Chandras, K. P. Karalis, and S. J. Khoury Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis J. Immunol., May 1, 2005; 174(9): 5407 - 5413. [Abstract] [Full Text] [PDF]
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Y.-F. Xia, B.-Q. Ye, Y.-D. Li, J.-G. Wang, X.-J. He, X. Lin, X. Yao, D. Ma, A. Slungaard, R. P. Hebbel, et al. Andrographolide Attenuates Inflammation by Inhibition of NF-{kappa}B Activation through Covalent Modification of Reduced Cysteine 62 of p50 J. Immunol., September 15, 2004; 173(6): 4207 - 4217. [Abstract] [Full Text] [PDF]
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 J. D. Hron, L. Caplan, A. J. Gerth, P. L. Schwartzberg, and S. L. Peng SH2D1A Regulates T-dependent Humoral Autoimmunity J. Exp. Med., July 19, 2004; 200(2): 261 - 266. [Abstract] [Full Text] [PDF]
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S. Dasgupta, M. Jana, Y. Zhou, Y. K. Fung, S. Ghosh, and K. Pahan Antineuroinflammatory Effect of NF-{kappa}B Essential Modifier-Binding Domain Peptides in the Adoptive Transfer Model of Experimental Allergic Encephalomyelitis J. Immunol., July 15, 2004; 173(2): 1344 - 1354. [Abstract] [Full Text] [PDF]
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 E. Kanters, M. J.J. Gijbels, I. van der Made, M. N. Vergouwe, P. Heeringa, G. Kraal, M. H. Hofker, and M. P. J. de Winther Hematopoietic NF-{kappa}B1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype Blood, February 1, 2004; 103(3): 934 - 940. [Abstract] [Full Text] [PDF]
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N. Nath, S. Giri, R. Prasad, A. K. Singh, and I. Singh Potential Targets of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor for Multiple Sclerosis Therapy J. Immunol., January 15, 2004; 172(2): 1273 - 1286. [Abstract] [Full Text] [PDF]
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S.-E. Lamhamedi-Cherradi, S. Zheng, B. A. Hilliard, L. Xu, J. Sun, S. Alsheadat, H.-C. Liou, and Y. H. Chen Transcriptional Regulation of Type I Diabetes by NF-{kappa}B J. Immunol., November 1, 2003; 171(9): 4886 - 4892. [Abstract] [Full Text] [PDF]
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D. Laderach, D. Compagno, O. Danos, W. Vainchenker, and A. Galy RNA Interference Shows Critical Requirement for NF-{kappa}B p50 in the Production of IL-12 by Human Dendritic Cells J. Immunol., August 15, 2003; 171(4): 1750 - 1757. [Abstract] [Full Text] [PDF]
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R. A. Corn, M. A. Aronica, F. Zhang, Y. Tong, S. A. Stanley, S. R. A. Kim, L. Stephenson, B. Enerson, S. McCarthy, A. Mora, et al. T Cell-Intrinsic Requirement for NF-{kappa}B Induction in Postdifferentiation IFN-{gamma} Production and Clonal Expansion in a Th1 Response J. Immunol., August 15, 2003; 171(4): 1816 - 1824. [Abstract] [Full Text] [PDF]
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S. Dasgupta, Y. Zhou, M. Jana, N. L. Banik, and K. Pahan Sodium Phenylacetate Inhibits Adoptive Transfer of Experimental Allergic Encephalomyelitis in SJL/J Mice at Multiple Steps J. Immunol., April 1, 2003; 170(7): 3874 - 3882. [Abstract] [Full Text] [PDF]
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D. Artis, K. Speirs, K. Joyce, M. Goldschmidt, J. Caamano, C. A. Hunter, and P. Scott NF-{kappa}B1 Is Required for Optimal CD4+ Th1 Cell Development and Resistance to Leishmania major J. Immunol., February 15, 2003; 170(4): 1995 - 2003. [Abstract] [Full Text] [PDF]
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U. Eriksson, M. O. Kurrer, I. Sonderegger, G. Iezzi, A. Tafuri, L. Hunziker, S. Suzuki, K. Bachmaier, R. M. Bingisser, J. M. Penninger, et al. Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis J. Exp. Med., February 3, 2003; 197(3): 323 - 331. [Abstract] [Full Text] [PDF]
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D. Artis, S. Shapira, N. Mason, K. M. Speirs, M. Goldschmidt, J. Caamano, H.-C. Liou, C. A. Hunter, and P. Scott Differential Requirement for NF-{kappa}B Family Members in Control of Helminth Infection and Intestinal Inflammation J. Immunol., October 15, 2002; 169(8): 4481 - 4487. [Abstract] [Full Text] [PDF]
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 B. Stoelcker, T. Hehlgans, K. Weigl, H. Bluethmann, G. E. Grau, and D. N. Mannel Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria Infect. Immun., October 1, 2002; 70(10): 5857 - 5859. [Abstract] [Full Text] [PDF]
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 J. Caamano and C. A. Hunter NF-{kappa}B Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions Clin. Microbiol. Rev., July 1, 2002; 15(3): 414 - 429. [Abstract] [Full Text] [PDF]
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C. Du, M. W. Khalil, and S. Sriram Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice J. Immunol., December 15, 2001; 167(12): 7094 - 7101. [Abstract] [Full Text] [PDF]
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 C. A. Jolly, A. Muthukumar, C. P. R. Avula, D. Troyer, and G. Fernandes Life Span Is Prolonged in Food-Restricted Autoimmune-Prone (NZB NZW)F(1) Mice Fed a Diet Enriched with (n-3) Fatty Acids J. Nutr., October 1, 2001; 131(10): 2753 - 2760. [Abstract] [Full Text] [PDF]
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