Neurochemical Mechanisms in Disease P32 potx

NF-κB in Brain Diseases 295
NF-κB transcription factors are expressed ubiquitously in mammalian cells.
Expression of multiple NF-κB family members has been reported in different
cells, including neurons and glial cells, of the central nervous system (CNS).
However, the role of the NF-κB family in the nervous system, both as media-
tors of transcriptional response to synaptic activity and in behavioral paradigms
of learning and memory, was found only recently. Investigating the functions of
NF-κB transcription factors in the CNS is now a new frontier, both for the general
field of NF-κB research and for understanding of transcriptional regulation in the
brain.
2 Structure of NF-κBandIκB Family
NF-κB transcription factors are highly conserved across species. In mammals, the
NF-κB family consists of five members: p50 (product of the NF-κB1 gene), p52
(product of the NF-κB2 gene), p65 (also known as RelA), c-Rel, and RelB. They all
share a Rel homology domain (∼300 amino acids in length) and, thus, the NF-κB
family is also known as the Rel family, in reference to c-Rel that was first discovered
as a proto-oncogene. This Rel domain contains the crucial functional region for
DNA binding, dimerization, nuclear localization, and interaction with the inhibitors
of NF-κB(IκB) (Fig. 1, top). The NF-κB family members function as dimers, and
the five subunits can homodimerize or heterodimerize. Many, but not all, of the
possible homodimer and heterodimer combinations have been observed in cells.
The NF-κB family can be classified into two subgroups, based on the presence or
absence of a transcriptional activation domain. p50 and p52 do not contain distinct
transcription activation domain and are, therefore, categorized class I. The homod-
imers of p50 and p52, and the p50/p52 heterodimer may occupy the NF-κB–binding
sites of DNA and, thus, function as repressors of gene transcription (Franzoso et al.,
1992). The three other NF-κB family members, p65, c-Rel, and RelB, constitute the
class II subgroup. NF-κB dimers containing one or two of these polypeptides act as
activators of transcription by virtue of the presence of at least one transcription acti-
vation domain. The two most abundant and biologically well-characterized NF-κB
dimers are p50 homodimer and p50/p65 heterodimer.

NF-κB exists in the cytoplasm in an inactive form via association with the
inhibitor of NF-κB(IκB) proteins. Six IκB members have been characterized (Fig. 1,
middle): IκBα,IκBβ,IκBε,Bcl-3,IκBζ, and IκBγ. The most prominent ones are
IκBα,IκBβ, and IκBε. This group of proteins contains either six or s even ankyrin
repeats, a 33-aa motif that mediates protein–protein interactions. The ankyrin
repeats in IκBα,Iκ
Bβ, and IκBε are flanked by two segments, the amino-terminal
signal response domain (SRD) and the carboxyl-terminal acidic region, which is
rich in prolines, glutamates, serines, and threonines (PEST). The SRD and the PEST
sequence have been shown to be essential for interactions with NF-κB dimers (Ernst
et al., 1995; Malek et al., 1998). The N-terminus of IκB also contains the nuclear
export signal (NES) that functions to constantly expel the NF-κB/IκB complex from
the nucleus (Huang and Miyamoto, 2001).
296 C X. Gong
Fig. 1 Domains of the NF-κBandIκB families. Top,theNF-κB transcription factors are divided
into two subgroups, Class I and Class II, depending on the presence or absence of transcription
activation domains. The Rel homology region is indicated with the amino-terminal domain in red
and dimerization domain in green. Other structural elements of interest such as nuclear local-
ization sequence (NLS) are also labeled. Middle,theIκB family members are aligned according
to ankyrin repeats. The amino-terminal signal response domain (SRD) and the carboxyl-terminal
acidic region rich in prolines, glutamates, serines, and threonines (PEST) are indicated. P and Ub
indicate the sites for inducible phosphorylation and ubiquitination, respectively. Bottom, p105 and
p100 proteins contain p50 and p52, respectively, in the amino-terminal half and ankyrin repeats in
the carboxyl-terminal half. The carboxyl-terminal half of p105 is homologous to IκBγ. (Modified
from Huxford et al., 1999, with permission from Cold Spring Harbor Laboratory Press)
NF-κB in Brain Diseases 297
Interestingly, two larger proteins, p105 (also called NF-κB1) and p100 (NF-κB2),
contain the Rel homology region of p50 and p52 in their amino-terminal half and the
ankyrin repeats in their carboxyl-terminal half (Fig. 1, bottom). Evidence suggests
that p50 and p52 are actually derived from p105 and p100, respectively, by prote-

olytic processing, so that p105 and p100 are sometimes called precursors of p50 and
p52. I κBγ can also be generated by proteolytic processing from p105. Full-length
p105 and p100 act as IκB as well (Naumann et al., 1993).
3 General Biological Role of NF-κB
NF-κB transcription factors promote the expression of over 200 genes involved in
a variety of cellular processes, indicating that they play important roles in multiple
aspects of biology. In addition, many more genes have the NF-κB–binding sequence
in their promoters, which have not yet clearly been shown to be controlled by
NF-κB. These NF-κB–regulating and potentially NF-κB–regulating genes and their
original references are listed comprehensively on the website of Dr. T. D. Gilmore
of Boston University ( These
genes can be divided into the following groups: (1) cytokines/chemokines and
their modulators; (2) immunoreceptors; (3) proteins involved in antigen presen-
tation; (4) cell adhesion molecules; (5) acute phase proteins; (6) stress response
genes; (7) cell surface receptors; (8) apoptosis regulators; (9) growth factors, lig-
ands, and their modulators; (10) early response genes; (11) transcription factors;
(12) viruses; (13) enzymes; and (14) miscellaneous genes not fitting into the groups
above. Although the functionally important NF-κB–binding sites are located in the
promoter/enhancer region of all these genes, the transcription of individual genes
and the amount of transcribed product after NF-κB activation under specific cir-
cumstances depend on many factors, including the composition of NF-κB dimers,
the nature of the NF-κB activating stimulus, and the number of consensus sites in
the target gene. In addition, NF-κB works in cooperation with other transcription
factors, especially activator protein-1 (Karin et al., 2001; Zhou et al., 2001).
Studies using gene knock-out animal models have revealed both specific and
redundant functions of each NF-κB family member in regulation of cell survival
and immune responses. For instance, the deletion of the p65 (RelA) gene in mice
causes embryonic lethality due to extensive apoptosis in the liver (Beg et al., 1995),
indicating that the function of p65 cannot be compensated for by other NF-κBfam-
ily proteins and is essential for the survival of the mouse embryo. On the other hand,

mice lacking p50 or RelB are immunodeficient but otherwise develop normally to
adulthood (Burkly et al., 1995; Sha et al., 1995; Weih et al., 1995). The knock-
out of multiple members of the NF-κB family results in more severe phenotypes,
which suggests that there is some functional redundancy between the NF-κB family
members.
NF-κB is essential for normal functioning of the immune system. It plays key
roles in regulating the expression of many cytokines, which are critical media-
tors of the immune system and are crucial for immune cell communication and
298 C X. Gong
effector functions during an active immune response. Studies on c-Rel–deficient
mice have demonstrated that c-Rel is essential for IL-2, IL-3, GM-CSF, and
γ-IFN expression in T lymphocytes; IL-6 expression in B cells; TNF-α expression
in macrophages; and IL-12 expression in dendritic cells (Gerondakis et al., 1996;
Liou et al., 1999; Sanjabi et al., 2000; Weinmann et al., 2001). When p105/p50
is knocked out, functional defects in the immune system appear despite otherwise
normal development and phenotype (Sha et al., 1995). P105/p50 is essential for the
survival of nonactivated B cells but not for all B cell-activated pathways (Snapper
et al., 1996; Grumont et al., 1999). C-Rel knock-out mice show normal development
but have B and T cell deficiencies (Kontgen et al., 1995). Mice deficient in the NF-
κB2 gene (p100/p52) mainly have defects in lymph nodes and splenic architecture,
although development is normal (Caamano et al., 1998). All these studies demon-
strate the vital role of NF-κB in normal development and functioning of the immune
system.
The activation of NF-κB is a double-edged sword. Although needed for proper
development and immune system function, NF-κB, if inappropriately overactivated,
can mediate inflammation and tumorigenesis. That duality is especially striking
in relation to cancer, a proinflammatory disease. Most inflammatory agents medi-
ate their effects through the activation of NF-κB, and the latter is suppressed by
anti-inflammatory agents. Similarly, most carcinogens and tumor promoters acti-
vate NF-κB, whereas chemopreventive agents suppress it, suggesting its strong

linkage with cancer. Paradoxically, most agents, including cytokines, chemother-
apeutic agents, and radiation that induce apoptosis, also activate NF-κB(Beg
and Baltimore, 1996). Thus, NF-κB is a part of the cells’ autodefense mecha-
nism and may mediate desensitization, chemoresistance, and radioresistance (Wang
et al., 1999).
The most studied role of NF-κB to date is its role in malignant transformation
and hyperplasia, in the control of apoptosis, and in immune functions. Some NF-κB
proteins act as oncogenes. C-Rel consistently transforms cells in culture, is itself
activated by a retroviral promoter insertion in an avian B cell lymphoma, and is
frequently amplified in Hodgkin’s lymphoma, diffuse large B cell lymphomas, and
some follicular and mediastinal B cell lymphomas (Gilmore et al., 2004). Several
oncogenes mediate their effects by activating NF-κB. Among them are oncogenic
Ras (Mayo et al., 2001; Kim et al., 2002) and c-myc (Kim et al., 2000). It has
been shown that NF-κB activation induces cellular transformation, proliferation,
invasion, and angiogenesis, and mediates metastasis (reviewed by Aggarwal, 2004).
On the other hand, functional blockage of NF-κB in transgenic murine and human
epidermis produced hyperplastic epithelium in vivo (Seitz et al., 1998). Selective
inhibition of NF-κB signaling in murine skin resulted in the spontaneous develop-
ment of squamous cell carcinomas (Seitz et al., 1998
; van Hogerlinden et al., 1999).
NF-κB blockage also triggered invasive human epidermal neoplasia (Dajee et al.,
2003). It appears that either overactivation or inactivation of NF-κB may lead to
tumorigenesis, depending on circumstances. It is possible that NF-κB has diff erent
roles in different cell types. The role of NF-κB in tumorigenesis has been reviewed
elsewhere recently (Aggarwal, 2004).
NF-κB in Brain Diseases 299
NF-κB also has a dual effect on controlling apoptosis. Because NF-κB regulates
the expression of many genes involved in apoptosis, the regulation of apoptosis by
NF-κB is very complicated and is far from being elucidated. The NF-κB signal-
ing pathway has emerged as a critical regulator of the apoptotic response. In most

circumstances, NF-κB is antiapoptotic, by activating the expression of antiapoptotic
genes, but it can also promote apoptosis in response to certain death-inducing signals
in certain cell types reviewed by (Kucharczak et al., 2003).
4 Regulation of NF-κB Signaling
NF-κB transcription factors are expressed ubiquitously in all cell types, but nor-
mally they are present as an inactive complex in the cytoplasm via their noncovalent
interaction with IκB. In response to varieties of stimuli, including cytokines, viral
and bacterial pathogens, and stress-inducing agents, the latent cytoplasmic NF-
κB/IκB complex is activated by phosphorylation on the conserved serine residues
in the amino-terminal portion of IκB. Phosphorylation targets IκB for ubiquitina-
tion, which leads to degradation of the IκB by the 26S proteasome. Degradation
of IκB releases NF-κB by unmasking the nuclear localization signal present in
the Rel-family polypeptides that permits translocation to the nucleus and binds
to its cognate DNA-binding site (5

-GGGRNNYYCC-3

) in the promoter/enhancer
regions of specific genes (Fig. 2).
Phosphorylation of IκB is catalyzed by a multimeric complex referred to as IκB
kinase (IKK), which is activated by various stimuli. The IKK complex consists of
two catalytic subunits (IKK-α and IKK-β) and a regulatory subunit IKK-γ or NF-κB
essential modulator (NEMO) (DiDonato et al., 1997; Zandi et al., 1997; Rothwarf
et al., 1998; Yamaoka et al., 1998). The activated IKK complex recruits IκBpro-
teins and phosphorylates them at serine residues (in the case of IκB-α, Ser32 and
Ser36 are phosphorylated). IKK can be phosphorylated and activated by another
kinase called NF-κB–inducing kinase (NIK), which may be involved in an NF-κB–
inducing signaling cascade induced by tumor necrosis factor (TNF) (Malinin et al.,
1997).
The activation of IKK is considered a major mechanism of NF-κB activation in

the classical pathway. However, in certain cases, such as in response to shortwave
UV light (Li and Karin, 1998; Kato et al., 2003), pervanadate (Mukhopadhyay et al.,
2000), H
2
O
2
(Takada et al., 2003), hypoxia/reoxygenation (Fan et al., 2003), nerve
growth factor (NGF) (Bui et al., 2001), erythropoietin (Digicaylioglu and Lipton,
2001), and Her-2 (Pianetti et al., 2001), the activation of NF-κB does not seem to
involve phosphorylation of IκB by IKK or even IκB degradation.
Studies have shown that NF-κB signaling is also regulated by phosphoryla-
tion of Rel proteins themselves. RelA (p65), the most dominant NF-κB protein, is
phosphorylated by cAMP-dependent protein kinase at Ser276, which enhances its
transcription function (Zhong et al., 1997). RelA phosphorylation can occur before
IκB degradation, which creates a moiety that is primed and “sitting on ready.” In
some cases, the phosphorylation of RelA can occur after the dissociation from IκB
300 C X. Gong
Fig. 2 Major pathway of NF-κB activation. NF-κB dimer (e.g., p50/p65 dimer) is normally i n a
latent form as a result of the association with the inhibitory protein IκB, which masks the nuclear
localization signal and DNA-binding domains of NF-κB and retains NF-κB in the cytosol. Inducing
stimuli (e.g., cytokines, synaptic transmission, and growth factors) activate the IκB kinase complex,
which rapidly phosphorylates IκB, leading to its degradation through the ubiquitin-dependent pro-
teasome pathway. Degradation of IκB by the 26S proteasome then allows NF-κB to translocate to
the nucleus and activate transcription of target genes. (Reproduced from Meffert and Baltimore,
2005 with permission from Elsevier)
(Zhong et al., 1997; Wang et al., 2000). The requirement for both phosphorylation
of RelA and degradation of IκB may set up a two-step mechanism that could serve
to integrate disparate signals. It could also be a failsafe algorithm to place more
stringent control on a powerful cellular agent to prevent inadvertent activation. In
addition, ceramide has been reported to activate NF-κB via activating atypical pro-

tein kinase C that, in turn, phosphorylates Ser311 of RelA (Duran et al., 2003). The
p38 MAPK was also shown to be required for NF-κB–dependent gene expression
(Carter et al., 1999).
In the CNS, IκB-α is the most prominent member of its class, but IκB-β and
IκB-γ also play supporting roles. IκB-γ is actually either encoded by alternative
mRNA species derived from the gene for p105 or produced by proteolytic cleavage
of p105 protein (Inoue et al., 1992; Heron et al., 1995). Full-length p105 and p100
can act as IκB as well (Naumann et al., 1993). Some of the previously characterized
NF-κB activators have unique roles in the CNS that might be relevant in determin-
ing the function of neuronal NF-κB transcription factors. For instance, the cytokine
TNFα could be a mediator of neuronal plasticity in noninflammatory settings of the
hippocampus (Beattie et al., 2002). Although the free radical nitric oxide is involved
NF-κB in Brain Diseases 301
in cell-mediated killing in the immune system, its alternative CNS role in regulating
synaptic efficacy is well documented; see the review by (Schuman and Madison,
1994). NF-κB can also be activated by stimuli specific to the nervous system, such
as β-amyloid, NGF, and neurotransmission. However, current knowledge of NF-κB
activation in the CNS is very limited.
5 Role of NF-κB Signaling in the CNS
5.1 NF-κB in the CNS
The key functions of the CNS are information transmission, processing, and storage.
Neurons communicate with each other via synapses, which are specialized cellu-
lar compartments consisting of presynaptic (sending) and postsynaptic (receiving)
parts. Neuronal function is supported and assisted by glial cells. NF-κB transcription
factors are present in both neurons and glial cells, including synapses of the neurons.
The p50/p65 dimer is the major NF-κB in the CNS, which is either constitutively
active or forms a complex with IκB. In addition, there are other NF-κB–binding
proteins in the brain, such as brain-specific transcription factor specifically detected
in the gray matter (Korner et al., 1989), developing brain factors enriched highly in
developing cortex (Cauley and Verma, 1994), and neuronal NF-κB–binding factor

with different target sequence requirements (Moerman et al., 1999). These NF-κB
binding factors were not assigned to specific genes, nor could they be tested directly
in reporter gene assays. It appears that an additional level of complexity is added by
overlapping mutually exclusive or synergistically acting binding sites of NF-κBfor
other transcription factors in the CNS.
5.2 Activators and Inhibitors of NF-κB in the CNS
Many activators of NF-κB have been identified (see the review by Kaltschmidt et al.,
2005), some of which are only seen in the nervous system, such as glutamate act-
ingasanNF-κB activator via the main ionotropic glutamate receptors or NGF via
the p75 receptor (Carter et al., 1996). In microglia, all neurotrophins activate NF-κB
(Nakajima et al., 1998). Some molecules, such as TNF, can both activate and repress
NF-κB in neurons, depending on the cell types and circumstances (Kaltschmidt
et al., 1999).
Several anti-inflammatory cytokines that are known from the immune system
inhibit NF-κB in the nervous system, but how these molecules act in the neuron is
not well understood. One possibility might be the induction of IκB transcription.
Some molecules have dual activity in regulating NF-κB, depending on their con-
centrations. A recent review has summarized the inhibitors of NF-κB in the nervous
system (Kaltschmidt et al., 2005).
302 C X. Gong
5.3 NF-κB–Regulating Genes in the CNS
As discussed above, there are many genes whose expression is regulated by NF-
κB, and this list of genes is still growing. Most of the NF-κB–regulating genes
are identified from studies in nonneuronal cells. Only a limited number of genes
that are regulated by brain NF-κB and with direct relevance for the nervous sys-
tem have been described. They include neural cell adhesion molecule (Simpson and
Morris, 2000; Liu et al., 2003), inducible nitric oxide synthase (Madrigal et al.,
2001), amyloid precursor protein (Grilli et al., 1995), μ-opioid receptors (Kraus
et al., 2003), brain-derived neurotrophic factor (Lipsky et al., 2001), inducible
cyclooxygenase-2 (Kaltschmidt et al., 2002), Ca

2+
/calmodulin-dependent protein
kinase IIδ (Kassed et al., 2004), galanin receptor (Lorimer et al., 1997), neuropep-
tide Y-Y1 receptor (Musso et al., 1997), and myelin basic protein (Paez et al., 2006).
With the increasing interest in studies of the role of NF-κB in the CSN, there is no
doubt that more genes will be found to be regulated by NF-κB in the brain. Many
NF-κB–regulating genes that were observed in nonneuronal cells are probably also
regulated by NF-κB in the brain.
5.4 Role of NF-κB in Synaptic Transmission
and Neuronal Plasticity
Neuronal plasticity is essential for the transfer and storage of information by neu-
rons. Recent studies have suggested that NF-κB may be crucially involved in the
important process of neuronal plasticity. The capability of NF-κB in transmitting
information from active synapses to the nucleus is supported by several studies
demonstrating the presence of NF-κB in synapses (Kaltschmidt et al., 1993; Meberg
et al., 1996; Meffert et al., 2003). A robust increase of p65 mRNA was observed after
long-term potentiation in vivo (Meberg et al., 1996). This increase might be part of
a feedforward mechanism leading to increased DNA-binding to the κB elements
during long-term potentiation (LTP). NF-κB is activated in neurons by glutamate,
an important synaptic neurotransmitter, and depolarization (Guerrini et al., 1995;
Kaltschmidt et al., 1995). Memory consolidation in crabs also involves the activa-
tion of NF-κB–like activity (Freudenthal et al., 1998). In rat, traumatic brain injury
first activates axonal NF-κB, and later, the activated NF-κB in the nuclei is detected,
and this activation could be detected as long as one year after brain injury (Nonaka
et al., 1999). In glutamate-stimulated hippocampal neurons, the return of p65 from
neuritic to nuclear distribution was observed (Wellmann et al., 2001; Meffert et al.,
2003).
Unlike most other cells, NF-κB is constitutively activated, which appears to be
the result of synaptic activity (Kaltschmidt et al., 1994). The basal constitutive NF-
κB activity in neurons could be repressed by specific inhibitors of action potential

generation, glutamate receptors, and L-type Ca
2+
channels (Meffert et al., 2003).
This suggests that extracellular influx of Ca
2+
, either through NMDA receptor or
L-type Ca
2+
channels, could activate NF-κB (Kaltschmidt et al., 2005). A pivotal
NF-κB in Brain Diseases 303
role for NF-κB in synaptic plasticity was further supported by studies in which
blockade of NF-κB activation impairs synaptic plasticity (Albensi and Mattson,
2000). A recent study reported that p50 knock-out mice exhibit impaired learning
ability (Kassed et al., 2002). Taken together, NF-κB may act as a signal trans-
ducer to transmit information from active synapses to the nucleus in addition to
its well-known role as a transcription factor, which transduces a synaptic signal into
a transcription event.
5.5 Role of NF-κB in Learning and Memory
NF-κB appears to be involved in translating short-term signals from distant sites in
neurites into long-term changes in gene expression, which may play a key role in
plasticity, development, and survival. Double knock-out of p65 and TNF-RI results
in a severe learning deficit (Meffert et al., 2003). A modulation of learning and
memory was also observed in two other transgenic mouse models where NF-κBwas
repressed by tetracycline-regulated expression of dominant negative IκBα (Meffert
and Baltimore, 2005). This nondegradable IκB remains bound to NF-κB and sup-
presses all NF-κB activation. In a recent study, repression of NF-κBbyIκBin
neurons resulted in behavioral deficits and a reduction in LTP and LTD induction
(Kaltschmidt et al., 2006), which occurs via protein kinase A/CREB signaling. On
the other hand, IκB expression driven by the prion promoter resulted in enhanced
learning in older animals (Meffert and Baltimore, 2005). It is possible that neuronal

NF-κB at physiological levels is needed for learning, but inhibition of pathological
NF-κB hyperactivation in elder age might enhance learning. Overall, a consensus of
behavioral studies in both crabs and mice suggests that, in most settings, NF-κB
plays a positive role in learning and memory and that general or p65-subunit–
specific inhibition of NF-κB function can lead to deficits in a variety of learning
paradigms.
5.6 Role of NF-κB in Neuroprotection
Because NF-κB generally has antiapoptosis action, its activation is critical to neu-
ronal survival. Several neurotrophic factors and cytokines may promote neuronal
survival by NF-κB activation. Trophic factor deprivation has been found to result in
a rapid and sustained increase in the level of IκB-α and IκB-β in cultured cerebellar
granule neurons and to lead to sustained inhibition of NF-κB (Kovacs et al., 2004).
A peptide inhibitor of NF-κB blocked the ability of NGF to prevent death of cul-
tured sympathetic neurons (Maggirwar et al., 1998), suggesting a role of NF-κBin
the control of neuronal death during development of the nervous system. When NF-
κB is inhibited, cultured PC12 cells go to apoptosis, and NGF is unable to prevent
it (Taglialatela et al., 1997). The cytokine-transforming growth factor-β1(TGF-β1)
may prevent neuronal apoptosis via an NF-κB-mediated mechanism, because this
ability is blocked by NF-κB decoy DNA (Zhu et al., 2004).
304 C X. Gong
The molecular mechanism by which NF-κB enhances neuronal viability is far
from fully understood. The majority of the studies have focused on the direct bind-
ing and activating of prosurvival genes by NF-κB. These genes fall into three broad
classes: antiapoptotic proteins, antioxidants, and neurotrophic factors. In addition
to the conventional transcriptional inductions of prosurvival genes, NF-κB appears
to have other viability-enhancing means at its disposal. For example, glucocorticoid
receptor agonists have neurodegenerative effects through inhibition of glucose trans-
port (Sapolsky, 1996). RelA inhibits the transcriptional activity of glucocorticoid
receptors through direct binding (Ray and Prefontaine, 1994).
The roles of NF-κB in neuronal survival are complex. Mice lacking the p50 sub-

unit of NF-κB exhibit increased neurotoxin-induced damage to neuronal cells as
compared to wild-type mice (Yu et al., 1999), but decreased damage following a
focal ischemic stroke (Nurmi et al., 2004). It was observed that activation of NF-κB
is correlated with neurotoxicity in other paradigms. It is possible that the trophic
or toxic dichotomy of NF- κB could be attributed to the specific subunits of the
activated complex and the differential regulation in different types of cells.
5.7 Role of NF-κB in Glial Cells
Regardless of any direct role of NF-κB in neuronal cells, its activity in glia could
dramatically influence neuroplasticity. Astrocytes play important roles in the modu-
lation of synaptic activity. Hence, changes in gene expression in astrocytes could
alter these processes, and NF-κB is as likely as any other factor to effect such
changes. In fact, NF-κB is involved in an elevation of astrocytic major glutamate
transporters (EAAT2) by epidermal growth factor (EGF) (Zelenaia et al., 2000;Su
et al., 2003), brain-derived neurotrophic factor (BDNF), and subtoxic dose of Aβ
(Rodriguez-Kern et al., 2003).
As the CNS representatives of the monocytic cell lineage, microglia undergo an
inflammatory type of activation in response to brain injury and stress. Among the
products of microglia activated by inflammatory signals is nitric oxide, which is
produced by the exquisitely NF-κB–sensitive, inducible nitric oxide synthase. This
enzyme can be elevated in an NF-κB-dependent manner in astrocytes (Akama et al.,
1998). Microglial activation is associated with a marked increase in expression of
cyclooxygenase-2, an oxyradical-generating enzyme, and agents that inhibit NF-κB
can suppress lipopolysaccharide-induced cyclooxygenase-2 expression, suggesting
an important role of NF-κB in microglial activation and oxyradical production.
The role of microglial NF-κB in neuronal injury is complicated by elevated
production of neurotrophic factors by the activated microglia. Activated microglia
produce NGF, basic fibroblast growth factor (bFGF), and TNF, each of which has
been shown to prevent neuronal death in various experimental models of neu-
rodegenerative diseases. A potent inducer of NF-κB activation in astrocytes is
bradykinin, an inflammatory mediator produced in the brain in response to ischemia

and trauma (Schwaninger et al., 1999). Acting through an NF-κB–mediated path-
way, bradykinin induces IL-6 production in astroctyes, which stimulates production
of several inflammation-related cytokines.