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MAPK Signal Transduction Underlying Brain Inflammation and Gliosis as Therapeutic Target.

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THE ANATOMICAL RECORD 292:1902–1913 (2009)
MAPK Signal Transduction Underlying
Brain Inflammation and Gliosis as
Therapeutic Target
Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology,
Warsaw, Poland
A majority, if not all, acute and progressive neurodegenerative diseases
are accompanied by local microglia-mediated inflammation, astrogliosis,
infiltration of immune cells, and activation of the adaptive immunity. These
processes progress by the expression of cytokines, adhesion molecules, proteases, and other inflammation mediators. In response to brain injury or
infection, intracellular signaling pathways are activated in microglia, which
turn on inflammatory and antigen-presenting cell functions. Different extrinsic signals shape microglial activation toward neuroprotective or neurotoxic phenotype under pathological conditions. This review discusses recent
advances regarding molecular mechanisms of inflammatory signal transduction in neurological disorders and in in vitro models of inflammation/gliosis.
Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine
protein kinases responsible for most cellular responses to cytokines and
external stress signals and crucial for regulation of the production of inflammation mediators. Increased activity of MAPKs in activated microglia and
astrocytes, and their regulatory role in the synthesis of inflammatory cytokines mediators, make them potential targets for novel therapeutics. MAPK
inhibitors emerge as attractive anti-inflammatory drugs, because they are
capable of reducing both the synthesis of inflammation mediators at multiple levels and are effective in blocking inflammatory cytokine signaling.
Small molecule inhibitors targeting of p38 MAPK and JNK pathways have
been developed and offer a great potential as potent modulators of brain
inflammation and gliosis in neurological disorders, where cytokine overproduction contributes to disease progression. Many of the pharmacological
MAPK inhibitors can be administered orally and initial results show therapeutic benefits in preclinical animal models. Anat Rec, 292:1902–1913,
C 2009 Wiley-Liss, Inc.
2009. V
Abbreviations used: AP-1 ¼ activator protein 1; APC ¼
antigen-presenting cells; ARE ¼ AU-rich element; ASK ¼
apoptosis signal-regulating kinase; ATF-2 ¼ activating
transcription factor 2; CRE ¼ cyclic AMP-responsive element;
CBP ¼ CREB binding protein; CsA ¼ ciclosporin A; ERK ¼
extracellular signal-regulated kinase; iNOS ¼ inducible nitric
oxide synthase; ISRE ¼ interferon-stimulated response element;
JNK ¼ c-Jun N-terminal kinase; LPS ¼ lipopolysaccharide;
MCAO ¼ middle cerebral artery occlusion; MCP-1 ¼ monocyte
chemoattractant protein 1; MAPKAP-K2 ¼ MAP kinaseactivated protein kinase 2/3; MEK ¼ MAP/ERK kinase; MKK ¼
MAP kinase kinase; MAP3K ¼ MAP kinase kinase kinase;
MLK ¼ mixed lineage kinase; MMPs ¼ metalloproteinases;
MyD88 ¼ myeloid differentiation factor 88; NIK ¼ NF-Binducing kinase; PAK ¼ p21-activated kinase; STAT ¼ signal
transducers and activators of transcription; TAK1 ¼
transforming growth factor-activated kinase 1; TBP ¼ TATA
box binding protein; TGF ¼ transforming growth factor; TLR
¼ Toll-like receptors; TNF ¼ tumor necrosis factor; TRAF ¼
TNF receptor-associated factor; TRIF ¼ Toll/IL-1R domaincontaining adaptor-inducing IFN-beta
Grant sponsors: Ministry of Science and Higher Education
(Poland); Grant number: COST B30N N401 0475 and PBZ/
*Correspondence to: Bozena Kaminska, Department of Cell
Biology, Nencki Institute of Experimental Biology, 3 Pasteur
Str., 02-093 Warsaw, Poland. Fax: 822-53-42.
Received 18 February 2009; Accepted 28 July 2009
DOI 10.1002/ar.21047
Published online in Wiley InterScience (www.interscience.wiley.
Key words: neurodegeneration; microglia activation; brain
inflammation; gliosis; proinflammatory cytokines;
Toll-interleukin-1 receptor superfamily; signal
transduction; MAP kinases; transcription factors;
AP-1; NF-jB; STAT; small molecule inhibitors
Inflammation (from Latin inflamatio, to set on fire) is
a key process in the host defense system, the complex biological response of tissue to harmful stimuli, damaged
cells, or irritants. The initial response to harmful stimuli
within the central nervous system (CNS) is achieved by
the activation of resident microglial cells and is followed
by the production of inflammation mediators triggering
the increased movement of blood-derived immune cells
into the injured tissue (Hanisch and Kettenmann, 2007).
A cascade of strictly controlled biochemical events propagates and matures the inflammatory response, involving
various cells within the injured tissue, the local vascular
system, and the immune system. Chronic inflammation
leads to a progressive shift in the type of cells which are
present at the site of inflammation and is characterized
by both destruction and repair of the tissue. The loss of
control and prolonged inflammation can lead to a number of neurological diseases, including neurodegenerative
disorders such as Alzheimer’s disease, Parkinson’s disease, age-related macular degeneration, HIV-associated
dementia, brain trauma, and stroke (Stoll et al., 1998;
Danton and Dietrich, 2003; McGeer and McGeer, 2003,
2004; Van Eldik et al., 2007).
Inflammation can be triggered by several mechanisms:
1) neurons release bioactive peptides in response to pain
(Steinhoff et al., 2000); 2) damaged cells release intracellular proteins, such as heat-shock proteins (Basu and
Srivastava, 2000) or the high-mobility group 1 protein
(HMGB1) (Scaffidi et al., 2002), or purines such as ATP
(Davalos et al., 2005) that trigger cytokine production; 3)
shed or secreted products of microorganisms are sensed
through binding to soluble (complement system) or cellsurface receptors such as Toll family members (Toll-like
receptors, TLRs), peptidoglycan recognition proteins and
scavenger receptors (Elward and Gasque, 2003; Martinon and Tschopp, 2005).
Although inflammatory responses can differ in various
diseases, there is a common spectrum of genes and endogenous mediators involved, including growth factors,
inflammatory cytokines such as interleukin-1 b (IL-1b),
tumor necrosis factor (TNF)-a, interleukin-6 (IL-6), chemokines [Fractalkine, macrophage inflammatory factor
(MIP-1a,b, IL-8)], matrix metalloproteinases (MMPs),
lipid mediators, and toxic molecules such as nitric oxide
(NO) or free radicals (Cayrol et al., 2008). In addition to
degradation of extracellular matrix, MMPs cleave cytokines (e.g., TNFa, FasL) and chemokines from tissue
macrophages as well as from blood-derived monocytes,
amplifying inflammatory reactions. Prostaglandin E2
and neutrophil-derived defensins recruit lymphocytes;
leukotrienes attract antigen-presenting dendritic cells.
Activated lymphocytes further activate macrophages to
secrete proteases, eicosanoids, cytokines, reactive oxygen, and nitrogen intermediates (Nathan, 2002).
The common pathophysiological hallmarks of neurodegenerative disorders are activation of microglia and
astrogliosis, infiltration of immune cells, and activation
of the adaptive immune system (Gehrmann et al., 1995;
Stoll et al., 1998; Danton and Dietrich, 2003; McGeer
and McGeer, 2003; Dudal et al., 2004; Block and Hong,
2005; Koistinaho and Koistinaho, 2005; Eikelenboom
et al., 2006; Whitton, 2007). Massive trauma, postischemic or toxicity-related necrosis, hemorrhage can trigger
inflammatory responses, and resident microglia respond
rapidly to neuronal cell death (Morioka et al., 1993;
Block and Hong, 2005; Hanisch and Kettenmann, 2007;
Rogers et al., 2007). Murine and human microglia
express all TLRs reported to date (with exception of
TLR9 not detected in humans) and respond to typical
TLR stimuli by expressing a panel of innate immune
cytokines, and chemokines, as well as costimulatory and
MHC class I/II molecules (Olson and Miller, 2004). Furthermore, damaged or overactive neurons release or leak
purines, including ATP and UTP that activate corresponding receptors: mainly P2X4 and P2X7, but also
P2Y2, P2Y6, and P2Y12 expressed on microglia (Ohsawa
et al., 2007). Excessive neuronal release of glutamate
not only leads to neuronal death but also activates
microglia-expressing metabotropic glutamate receptors
(Taylor et al., 2002, 2005).
After initiation of inflammation, microglial cells not
only secrete large amounts of neurotoxic or proinflammatory cytokines (e.g., IL-1, TNF-a, IL-12, INF-c, FasL)
but also produce anti-inflammatory molecules such as
IL-10 or IL-1 receptor antagonist (Feuerstein et al.,
1997; Aloisi, 2001). Although the repertoire of synthesized cytokines, chemokines, and neurotrophic factors
determines a final outcome of inflammation, a massive
production of cytokines such as IL-1b or TNF-a is detrimental. The inhibition of their secretion or activity with
neutralizing antibodies or soluble cytokine receptors
decreases neuronal damage (Barone et al., 1997;
Schielke et al., 1998; Shohami et al., 1999; Rothwell and
Luheshi, 2000; Boutin et al., 2001; Aggarwal, 2003;
Rothwell, 2003; Simi et al., 2007).
Cytokines produced by microglia can activate astrocytes which in turn become important contributors to
inflammatory and immune responses within the brain
(Benveniste, 1998; Farina et al., 2007). Astrocyte activation (reactive astrogliosis) accompanies neuronal damage
and microglia activation after insults of different etiology, including stroke (Stoll et al., 1998). Reactive astrocytes proliferate, undergo hypertrophy of processes and
upregulation of intermediate filaments (Pekny and Nilsson, 2005), and produce neurotrophic substances, as well
Fig. 1. Activation of astrocytes and microglia in the brain following
transient ischemia. Staining with isolectin B4 and immunohistochemistry for glial fibrillary acidic protein (GFAP) reveals a strong microglial
activation and astrogliosis in the ischemic cortex in response to tran-
sient MCAO. Bar graphs show the number of stained cells in the ipsilateral cortex at indicated time after ischemia (means SEM, *P >
0.05, **P > 0.01).
as proinflammatory (IL-1, IL-6) and cytotoxic cytokines
(FasL, TNF-a) (Benveniste, 1998). Activated astrocytes
can produce toxic molecules such as reactive oxygen species and NO (for a review see Stoll et al., 1998). Figure 1
illustrates an increase in the number and morphological
alterations of lectin B4-positive microglia and GFAP-positive astrocytes in the ischemic hemisphere 72 hr after a
middle cerebral artery occlusion (MCAO). The significant
increase in the number of lectin B4-positive microglia
was observed as early as 6 hr after ischemia and progresses through the postischemic period (Fig. 1). TNFa
and IL-1b are upregulated in ischemic brain lesions
within 6–12 hr, primarily in microglial cells and at 24 hr
in astrocytes (Zawadzka and Kaminska, 2005).
Cytokines and chemokines released by microglia promote the recruitment of lymphocytes and macrophages.
Infiltration of peripheral macrophages and lymphocytes
is not restricted to infectious or autoimmune disorders of
the nervous system (Greter et al., 2005), but occurs in
response to cerebral ischemia and traumatic lesions.
Lymphocytic infiltration was observed in MCAO and
photochemically induced focal ischemia in the rat cortex
(Schroeter et al., 1994; Jander et al., 1995). Studies of
postischemic damage and neurological deficits in mice
deficient in lymphocytes (Rag1-/-), CD4þ T cells, CD8þ
T cells, B cells, or IFN-c revealed that infiltrating CD4þ
and CD8þ T lymphocytes and production of IFN-c contribute to the inflammatory and thrombogenic responses,
brain injury, and neurological deficits (Yilmaz et al.,
2006). Human studies indicate that stroke recurrence/
death rates were significantly associated with increasing
CD4þCD28-lymphocyte counts in peripheral blood
(Nadareishvili et al., 2004), and accumulation of CD4þ
T cells was detected in the brains of postmortem human
PD specimens (Brochard et al., 2009). These results indicate an involvement of the adaptive immune system in
progression of brain damage.
A detailed study of receptor-triggered signaling and
effector functions of microglia in vivo is difficult.
Although, microglia comprise 5%–15% of the resident
cell population of the CNS, current methods for isolating
Fig. 2. MAPK signaling in proinflammatory activation of microglia
in vitro. Microglial cells isolated as previously described (Zawadzka
and Kaminska, 2005) were activated by an addition of 100 ng/mL LPS
and 24 hr later labeled with the Coomasie blue (A) to visualize mor-
phological transformation; note the amoeboid morphology of activated
cells. LPS induces a rapid activation of MAPK in cultured microglial
cells (B) and upregulates the expression of inflammation-related genes
as evaluated by a quantitative real-time PCR (C).
these cells from adult brain are laborious and give low
yields. Thus, it is easier to prepare primary microglia
derived from mixed glial cultures established from neonatal mice and rats. The studies by Carson’s group demonstrated that cultured microglia display a much more
homogenous phenotype than in the brain, possibly due
to the homogenous environment of the culture plate
(Carson et al., 2007). However, the results from in vitro
culture may not be fully predictive of in vivo biology
because of the absence of environmental signals provided by healthy neurons and astrocytes. Despite of all
limitations, recent protocols allow for the isolation and
maintenance of microglia in cell cultures prepared from
rodents. Typically, glial primary cultures are prepared
from neonatal brains and involve propagation of microglia on astrocyte monolayer followed by shaking off
microglial cells and plating them on culture dishes for
nonadherent cells. A maintenance of microglial cells for
additional 48 hr results in silencing and the appearance
of a ramified morphology (Fig. 2). Various assays can be
performed to confirm macrophage-like functional activity, including morphological alterations, motility, phagocytosis, and inflammatory gene expression. BV-2,
murine-immortalized microglial cells, frequently used in
the studies of microglial function (Petrova et al., 1999),
under basal conditions are partly activated and do not
recapitulate all features represented by primary microglia cultures. Cultured microglial cells retain their plasticity as indicated by their ability to upregulate MHC
class II, differentiate into cells with a macrophage morphology following the addition of IFN-c and GM-CSF,
and synthesize proinflammatory cytokines and inflammation modulators (iNOS, Cox2) (Carson et al., 2007).
When stimulated with lipopolysaccharide (LPS), a bacterial wall component and inducer of monocytes/macrophages (alone or in combination with IFNc) microglial
cells develop a potent neurotoxic phenotype (Bal-Price
and Brown, 2001). Cultured microglia cells can also be
used to model Alzheimer-related degeneration. b-Amyloid (Abeta) has been shown to induce iNOS in cultured
microglia and kill cocultured neurons via an NO-dependent mechanism (Wisniewski and Wegiel, 1994). Fibrillar
Abeta1-42 peptides induced the expression of iNOS,
cytokines (TNF-a, IL-1b, and IL-6), and integrin
markers in mouse primary microglia via TLR2 receptors
(Jana et al., 2008). The establishment of protocols for
pure primary microglial cultures grossly facilitated studies of mechanisms of microglial activation and functions
involved in a variety of CNS pathologies.
Rodent primary astroglial cultures depleted of microglia and oligodendrocytes are used to study gliosis in
vitro. Astrocyte-enriched cultures can be subjected to
focal mechanical injury by a scraping of a cell layer or
once cultured on deformable SILASTIC membranes subjected to rapid, reversible stretch-induced injury. Inflammatory conditions can be imitated by the exposure of
rodent primary astrocyte cultures to a complete cytokine
mix (CCM) consisting of TNF-a, IL-1b, and IFN-c, which
results in an activated state associated with the release
of inflammatory mediators (Falsig et al., 2006). This
model recapitulates many aspects of a reactive astrocytosis, such as astrocytic hypertophy, upregulation of GFAP
Fig. 3. MAPK signaling in cytokine-stimulated hypertrophic astrocytes. Primary astrocytic cultures were isolated as previously
described (Zawadzka and Kaminska, 2003) and labeled in green with
anti-GFAP-FITC. Astrocytes were activated by an addition of IL-1b,
TNFa, and IFNc (each 100 ng/mL). Cytokine-stimulated astrocytes
become hypertrophic (A). An addition of the cytokine cocktail strongly
increased the levels of phophorylated MAPK (B) and stimulated the
NF-jB transcriptional activity in cells transiently transfected with the
luciferase reporter gene under control of the 5 NF-jB binding sites
(Fig. 3A), and chemokine and cytokine production, and
has been used by us and others to study astrocytic cytokine signaling. Figure 3B,C shows a rapid activation of
MAP kinases and upregulation of NF-jB-driven transcription, which leads to the production of inflammation
presence of a common intracellular Toll-IL-1 receptor
(TIR) domain. Adaptor proteins containing TIR domain
can be differentially recruited to the Toll-IL-1 receptors
and determine the specificity of signaling. These adaptors, include MyD88 (myeloid differentiation factor 88);
TIRAP (TIR-domain-containing adaptor protein); TRIF
(TIR-domain-containing adaptor protein inducing IFNb); and TRAM (TRIF-related adaptor molecule).
Activation of TLR4 triggers two major intracellular
pathways, the MyD88-dependent and MyD88-independent, TRAM-dependent pathways. The MyD88-dependent
pathway mainly induces proinflammatory cytokines
such as TNFa, IL-6 through activation of MAPK and
NF-jB. The TRAM-dependent pathway predominantly
induces type I interferons and chemokines such as IP-10
and interferon (IFN)-induced proteins through activation
of interferon regulatory factor (IRF) 3 or 7 and NF-jB
(Yamamoto et al., 2003). Both pathways complement
each other in the production of proinflammatory mediators. Genetic and biochemical studies revealed that
while most TLR and IL-1 receptor use the adaptor molecule MyD88 to mediate inflammatory signal transduction, double-stranded RNA triggered, TLR3-mediated
signaling is independent of MyD88 (Akira et al., 2006).
Signaling via Toll-TNF-Interleukin-1
Receptor Superfamily
In response to brain injury or infection, intracellular
signaling pathways are activated in microglia to carry
the signal needed to perform effector inflammatory and
APC functions. Primary inflammatory stimuli (microbial
products, protein aggregates, unfolded proteins) and
cytokines such as IL-1b and TNFa act through the Toll
receptors, IL-1 receptor (TIR) family or the TNF receptor
family, respectively (Olson and Miller, 2004). The Tollinterleukin-1 receptor superfamily is defined by the
The stimulation with LPS activates multiple TIR-domain-containing adaptors and induces pathways leading
to both NF-jB and IRF3 activation (Li and Qin, 2005).
TLR signaling results in the downstream activation of
three major families of proteins important in the activation of inflammatory gene expression: MAPK, nuclear
factor-jB (NF-jB)/Rel proteins and IFN regulatory factors. The MyD88-dependent pathway, which is used by
most TLRs, recruits IL-1R-associated kinase (IRAK)-1
and IRAK-4 and TNF receptor-associated factor 6
(TRAF6), which afterward dissociates from the receptor
complex and associates with another complex composed
of transforming growth factor b-activated kinase (TAK1)
and TAK1-binding protein 1. This complex formation
leads to the activation of TAK1, which in turn activates
the transcription factors NF-jB and activator protein 1
(AP-1) through the canonical IjB kinase (IKK) complex
and the mitogen-activated protein kinase pathway,
respectively (Li and Qin, 2005; Akira et al., 2006; Hu
et al., 2007; Uematsu and Akira, 2007).
A growing body of evidence demonstrates that activation through TLRs is involved in neurodegeneration
(Tang et al., 2007). TLR2-deficient mice develop
decreased CNS injury when compared with wild-type
mice after focal cerebral ischemia (Lehnardt et al.,
2007). TLR-4 deficiency protects mice against ischemia
and axotomy-induced retinal ganglion cell degeneration
(Kilic et al., 2008).
TNFa acts through two cell surface receptors: TNFR1
and TNFR2. Activation of TNFR1 leads to the recruitment of the adaptor TRADD (TNFR-associated DD),
which can further recruit receptor-interacting protein kinase 1 (RIP1) and TNFR-associated factors (TRAFs),
which trigger NF-jB activation, leading to cell survival
and proinflammatory responses. Recent studies demonstrated involvement of TRADD also in the TLR4 complex
formation after LPS stimulation. TRADD-deficient macrophages show impaired cytokine production in response
to LPS and poly (I:C) in vitro (Chen et al., 2008; Ermolaeva et al., 2008). TRAF6 has been implicated in mediating the signals from members of different receptor
families, including the TNF receptor superfamily, IL-1R/
Toll-like receptor superfamily (IL-1R/TLRSF), TGFbR,
IL-17R, and IL-25R, and the NOD-like pattern recognition receptors. TRAF6 activation leads to downstream
activation of PI3K, MAPK cascade, and the transcription
factors NF-jB, NFAT, and IRF (Aggarwal, 2003; Wu and
Arron, 2003).
Activation of NF-jB by the proinflammatory cytokines
and other stress-like stimuli requires the IKK complex,
which contains the kinases IKKa, IKKb, or IKKc and
the regulatory NEMO (NF-jB essential modulator) subunit (Li et al., 2002). Although IL-1b and TNFa both
require NEMO for classical NF-jB activation, NEMO
forms a functional IKK complex with IKKa in response
to IL-1b, but TNFa requires IKKb to form a signaling
unit (Solt et al., 2007).
Spatial and temporal separation of IKK and MAPK
signaling cascades determine biological specificity and
functional outcome in TNFR signaling (reviewed in
Bonizzi and Karin, 2004; Karin and Gallagher, 2009).
Lys48-linked ubiquitination of TRAF3 marks it for degradation by the proteasome that releases the brake on
TRAF2/6:MAP3K (the MAPK kinase kinase) complexes,
leading to their translocation from the cytoplasmic part
of the receptor to the cytosol where they initiate MAPK
phosphorylation and activation (Liao et al., 2004). The
relevant MAP3Ks and downstream kinases are illustrated in Fig. 4. TRAFs induce the phosphorylation of
MAP3K: MEKK1 at Thr1381 and TAK1 at Thr187 and
Thr184 within their activation loops (Matsuzawa et al.,
2008). MEKK1 phosphorylates MKKs 3, 4, 6, and 7, the
MAP2Ks that are responsible for JNK and p38 activation. This phosphorylation occurs within a matter of several minutes. More recently, gene ablation and short
hairpin RNA approaches have been used to identify and
verify several physiologically relevant MAP3Ks involved
in JNK and p38 activation by TNFR family members
(Karin and Gallagher, 2009). IKK activation proceeds
faster than MAPK activation, takes place at the receptor, and is independent of TRAF3 degradation.
MEKK1 is a major contributor to activation of JNK
and p38 by two B cell TNFR family members: CD40 and
BAFF receptor. CD40 forms a complex containing adaptor molecules TRAF2, Ubc13, and IKKc, which are
required for the activation of MEKK1 and downstream
MAPK cascade (Matsuzawa et al., 2008).
Signaling via MAP Kinase Cascades
Three major groups of distinctly regulated MAP kinase cascades that lead to altered gene expression:
ERK1/2, JNK, and p38 MAP kinase are known in
humans. ERK1/2 is activated by MKK1 and MKK2, JNK
by MKK4 and MKK7, and p38 MAP kinase by MKK3,
MKK4, and MKK6, respectively. Upon activation of the
MAP kinases, transcription factors present in the cytoplasm or nucleus are phosphorylated and activated,
leading to expression of target genes resulting in a biological response (Fig. 4). The multiple interactions
between the different MAP kinase cascades serve to
integrate the responses and activate separate sets of
genes (Pearson et al., 2001; Karin and Gallagher, 2009).
Termination of signal transduction and negative regulation of MAPK activity is executed primarily by MAPK
phosphatases (MKPs), a group of 11 dual-specificity
phosphatases (known also as DUSP) which dephosphorylate the MAPKs on their regulatory threonine and tyrosine residues. MKP-1 localizes to the nucleus and
preferentially dephosphorylates activated p38 MAPK
and JNK. Lack of MKP-1 affects the production of both
proinflammatory and anti-inflammatory cytokines after
LPS treatment (Chi et al., 2006).
MAPK Signal Transduction Is a Key Mediator
of the Production of Inflammation Mediators
The expression of proinflammatory cytokines can be
regulated at both the transcriptional and post-transcriptional levels (Kaminska, 2005; Clark et al., 2009). MAP
kinases are key mediators of eukaryotic transcriptional
responses to extracellular signals and control gene
expression via the phosphorylation and regulation of
transcription factors, coregulatory proteins and chromatin proteins (Whitmarsh, 2007). The most prominent
example is phoshorylation of c-Jun and ATF-2 proteins
by JNK and p38 MAPK leading to increased transcriptional activity of the AP-1 transcription factor. ETS-domain ternary complex factors (TCFs), including Elk-1
and SAP-1, are phosphorylated and activated by ERK,
Fig. 4. The mitogen-activated protein (MAP) kinase signal transduction pathway and its pharmacological modulation. MAPK family is
composed of three modules serially activated kinases: a MAPK kinase
kinase (MAP3K), a MAPK kinase and ERK, JNK and p38 MAPK. Several substrates or indirect targets of each pathway and their specific
inhibitors are indicated. Abbreviations: ATF, activating transcription
factor; ASK, apoptosis signal-regulating kinase; CBP, CREB binding
protein; CREB, cAMP response element binding protein; Elk-1, Etslike transcription factor; ERK, extracellular signal-regulated kinase;
Ets, transcription factor with v-ets domain (viral-E-26); GADD 153,
growth arrest and DNA damage-inducible protein 153; iNOS, inducible
nitric oxide synthase; JNK, c-Jun amino-terminal kinase; MAPKAP-K2,
MAP kinase-activated protein kinase 2; MEF, myocyte-enhancing factor; MEK, MAP/ERK kinase; MEKK, MEK kinase; MLK, mixed-lineage
protein kinase; MyD88, myeloid differentiation factor 88; NFAT4, nuclear factor of activated T cells 4; NIK, NF-jB-inducing kinase; PAK,
p21-activated kinase; TAK, transforming growth factor-b-activated protein kinase; TAO, one thousand and one amino acids; TGF-b, transforming growth factor b; TLR, Toll-like receptors; TBP, TATA box
binding proteins; TNF, tumor necrosis factor; Tpl-2, tumor progression
locus 2 kinase; TRAF, TNF receptor-associated factor; TRAM, TRIFrelated adaptor molecule; TRIF, Toll/IL-1R domain-containing adaptorinducing IFN-beta.
JNK, and p38, or ERK and p38, respectively, leading to
enhanced transcription of the c-fos gene (Yang et al.,
2003). Upregulation of immediate early genes such as cjun and c-fos followed by the formation of the AP-1 transcription factor is required to target promoter elements
of many genes (Whitmarsh, 2007). In many cases, coordination of multiple MAP kinase pathways is required to
upregulate cytokine expression. For example, a strong
induction of TNF promoter-driven gene expression was
observed when all of the four MAP kinase pathways
were activated simultaneously, suggesting a cooperative
effect among these kinases (Zhu et al., 2000).
Besides phosphorylation of transcription factors in the
nucleus, MAPK are involved in the regulation of several
kinases regulating the protein translation. ERK and p38
MAPK phosphorylate MAPK signal-integrating kinase 1
(Mnk1), which phosphorylates an eukaryotic initiation
factor 4E (eIF4E), crucial for the initiation of protein
synthesis. The p38 pathway has been implicated in the
regulation of mRNA stability of cyclooxygenase 2, TNFa, IL-3, IL-6, IL-8, MCP-1a, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial
growth factor, urokinase-type plasminogen activator, and
inducible NO synthase genes (Clark et al., 2003).
The effect of p38 MAPK on TNF-a, IL-6, and IFNc
synthesis is mainly mediated via the activation of MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2/MK2), because the LPS-induced production
of these cytokines is decreased by 90% in MK2-deficient
mice (Kotlyarov et al., 1999; Neininger et al., 2002). p38
MAPK a/b activates the nuclear MK2, and as a result of
this activation MK2 is exported from the nucleus to the
cytoplasm. Active MK2, in turn leads to the phosphorylation of its substrates, such as small heat shock protein
Hsp25/27, tyrosine hydroxylase, leukocyte-specific protein 1, and tristetraprolin (TTP). TTP is the only transacting factor shown to be capable of regulating adenine/
uridine-rich element (ARE)-dependent mRNA turnover
(Brooks et al., 2004). Recent studies using MK2- and
TTP-deficient mice demonstrated that TTP is the major
target of MK2 involved in the post-transcriptional
regulation of TNF. TTP binds ARE in the 30 -untranslated region of TNF mRNA and destabilizes TNF
mRNA. MK2 activity leads to stabilization of TTP
mRNA and increased TTP protein stability but reduced
affinity to ARE (Hitti et al., 2006).
Distinct Classes of Inhibitors of MAPK
Signaling Pathways
Since the discovery of p38 MAPK involvement in the
synthesis of IL-1b and TNFa in 1994 (Lee et al., 1994),
it was well established that the main biological consequence of p38 activation is the production of inflammatory mediators to initiate leukocyte recruitment and
activation. To date, four p38 MAP kinase isoforms have
been identified sharing about 60% homology. Two isoforms (p38a and p38b) are ubiquitously expressed, p38c
is predominantly expressed in skeletal muscle, whereas
p38d gene expression is found in the lung, kidney, testis,
pancreas, and small intestine. p38a is the major isoform
of p38 MAPK, activated under inflammatory conditions
and crucial for the production of inflammation mediators. p38 MAPK is activated by the dual phosphorylation
on Thr180 and Tyr182 by upstream MAPK kinases:
MKK3 and 6, which are activated by upstream MAP3Ks.
Extracellular signals activating the p38 MAP kinase
pathway include a variety of cytokines (IL-1a, IL-2, IL-7,
IL-17, IL-18, TGF-b, and TNF-a) and pathogenic stimuli,
including LPS, staphylococcal peptidoglycan and enterotoxin B, echovirus 1, and herpes simplex virus 1 (Olson
and Miller, 2004).
MAPK inhibitors emerge as attractive anti-inflammatory drugs, because they are capable of reducing both
the synthesis of inflammation mediators at multiple levels by transcriptional, post-transcriptional, and translational repression and are effective in blocking
proinflammatory cytokine signaling. Following the pioneering work with p38 MAPK inhibitors such as SB
203580 (developed by SmithKline Beecham), a vast number of inhibitors of MAPK (Fig. 4) has been characterized in vitro and in animal models, and several
compounds have been advanced into clinical trials.
The commonly used inhibitor SB 203580 is known to
inhibit both p38a and p38b isoforms by binding to the
ATP pocket of p38 MAPK. A second generation of p38
MAPK inhibitors shows a better selectivity. SB 239063
exhibits the equipotent inhibitory activity against the aand b-isoforms and no activity (up to 100 lM) against
the c- and r-kinase isoforms (reviewed in Kaminska and
Swiatek-Machado, 2008). Another class of inhibitors is
represented by BIRB 796 BS [1-(5-tert-butyl-2-p-tolyl2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphtalen1-yl]-urea], a water-soluble molecule developed by Boehringer Ingelheim Pharmaceuticals. In contrast to other
p38 MAPK inhibitors (e.g., SB 203580), BIRB 796 BS prevents both the phosphorylation and activity of p38 MAPK
by binding to a novel allosteric binding site as well as to
the ATP pocket of p38 MAPK. The studies in humans
demonstrated that the orally administered BIRB 796 BS
significantly inhibited LPS-induced p38 MAPK activation
in the leukocyte fraction, as well as cytokine production
(Branger et al., 2002).
Semapimod (formerly known as CNI-1493) is a synthetic guanylhydrazone (developed by Cytokine PharmaSciences), which inhibits MAPK signal transduction
pathway by preventing phosphorylation of MEK, p38
MAP kinase, and JNK via yet unknown mechanism
and affects the production of the proinflammatory cytokines TNFa, IL-1b, IL-6, MIP-1 a/b, and NO (Bianchi
et al., 1995; Cohen et al., 1996). Semapimod has been
shown to inhibit macrophage activation and to impair
maturation of dendritic cells associated with a reduction of DC-maturation marker (CD83) (Zinser et al.,
CEP-1347 (from Cephalon) is a potent inhibitor of
mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAP3K),
which acts upstream of p38 and JNK activation in macrophages (Maroney et al., 2001). CEP-1347 inhibited
MAPK-mediated neuronal death in vitro and in animal
models of neurodegenerative diseases. CEP-11004, a new
MLK inhibitor, efficiently inhibited TNF-a production in
LPS-stimulated THP-1 cells and BV-2 microglial cells, as
well as in mice when injected 2 hr prior to LPS administration (Ciallella et al., 2005). CEP-1347 and CEP-11004
blocked the activation of murine astrocytes by either
TNF plus IL-1 or by a CCM containing IFN-c. The compounds blocked production of NO, prostaglandin E2, and
IL-6 with a median inhibitory concentration (IC50) of
approximately 100 nM. Although CEP-1347 did not
affect the nuclear translocation of NF-jB, it blocked the
expression of Cox2, iNOS, TNF, GM-CSF, urokinase-type
plasminogen activator, and IL-6 at the transcriptional
level (Falsig et al., 2004).
SP600125, an anthrapyrazolone inhibitor of JNK
(developed by Celgene), is a reversible ATP-competitive
inhibitor. SP600125 effectively inhibited the phosphorylation of c-Jun, the production of IFNc, TNFa, and IL-10
and weakly affected IL-1b and IL-6 production in Th1
cells. In Th2 cells, SP600125 potently blocked TNFa and
IL-10 but had no effect on IL-4. In human peripheral
blood monocytes stimulated with LPS, SP600125
reduced elevation of COX-2 and TNFa mRNA in a dose-
dependent manner, while it had no effect on the levels of
ICAM-1, IL-1b, and IL-8 mRNA (Bennett et al., 2001).
PD098059 (20 -amino-30 -methoxyflavone), a MEK1 inhibitor, and UO126, 1,4-diamino-2,3-dicyano-1,4-bis(2aminophenylthio)butadiene, a dual MEK1 and MEK2
inhibitor, are selective inhibitors of ERK signaling pathway (Fig. 4). ERK signaling is activated by a wide variety of external signals leading to cell proliferation or
differentiation and cell survival (Pearson et al., 2001).
Inhibitors of p38 MAPK and JNK Signaling
Pathways as Neuroprotective Drugs
Inhibitors of p38 MAPK (e.g., SB 203580, RWJ 67657,
BIRB 796 BS) have been found to reduce LPS-induced
cytokine production in mice during systemic endotoxemia (Badger et al., 1996; Wadsworth et al., 1999) and
in the leukocyte fraction in human volunteers (Branger
et al., 2002). Sustained activation of p38a MAPK was
observed in activated microglia after cerebral brain ischemia, and its inhibitor SB 203580 significantly
reduced the infarct size in the gerbil global ischemia
model (Sugino et al., 2000). A second-generation p38
MAPK inhibitor, SB 239063, decreased the infarct volume and neurological deficit in rats after transient
(Legos et al., 2001) and permanent (Barone et al., 2001)
MCAO. SB 203580, delivered by the intraventricular
injection 30 min before, 6 or 12 hr after MCAO, reduced
the infarct volume and improved neurological deficits.
SB 203580 attenuated the expression of iNOS, TNFa,
IL-1b, and Cox-2 when administrated 6 hr after MCAO
(Piao et al., 2003).
Transgenic mice overexpressing APP751 (a transgenic
mouse model of Alzheimer’s disease) have increased
inflammatory responses and showed upregulation of
phosphorylation of p38 MAPK. Ab exposure has been
shown to stimulate p38 MAPK phosphorylation in cultured microglia (McDonald et al., 1998). SD282, an inhibitor of p38 MAPK, reduced activation of microglia
and protected the APP751-overexpressing mice against
ischemic injury (Koistinaho et al., 2002).
The MLK inhibitor CEP-1347 blocked the activation of
the c-Jun/JNK signaling pathway in neurons exposed to
stress and attenuated neurodegeneration in animal models of Parkinson’s disease (Saporito et al., 1999). The
studies by Lund et al. (2005) demonstrated that CEP1347 reduces cytokine production in primary cultures of
human or murine microglia and in monocyte/macrophage-derived cell lines, stimulated with endotoxins or
Ab1-40. Moreover, CEP-1347 inhibited TNF production
in the brain induced by intracerebroventricular injection
of LPS in mice.
In primary microglial cultures, SP600125 (1–5 lM)
JNK inhibitor reduced the LPS-induced metabolic activity and upregulation of Cox-2, TNF-a, MCP-1, and IL-6,
while inhibition of ERK1/2 by 40 lM PD98059 and p38a
by 5 lM SB 203580 had a more pronounced effect on
LPS-induced cellular enlargement.
Ciclosporin A (CsA, formerly cyclosporin A), FK506
(tacrolimus), and SDZ ASM 981 (pimecrolimus) are short
peptides used to block graft rejection in transplantation
of organs and bone marrow. They bind to specific
intracellular proteins called immunophilins and such
complexes inhibit calcineurin (PP2B, PP3), a calciumand calmodulin-dependent threonine/serine phosphatase.
FK506 and CsA exert the neuroprotective action in animal models of neurologic diseases: traumatic brain
injury, spinal cord injury, optic nerve crush, antiretroviral toxic neuropathy, rodent models of Parkinson’s disease, and stroke (reviewed in Guo et al., 2001;
Kaminska et al., 2004). We demonstrated that FK506 (1
mg/kg, i.v.) injection 1 hr after MCA occlusion greatly
reduces the activation of microglia and astrocyte in the
injured cortex, the infarct volume, and neurologic deficits. FK506 inhibited upregulation of IL-1b and TNFa
mRNA expression in the rat ischemic brain and in LPSstimulated microglial cultures (Zawadzka and Kaminska, 2005). Although immunosuppressants are not direct
MAPK inhibitors, our studies demonstrate that FK506
strongly inhibits LPS-induced activation of p38 MAPK
and JNK in microglial cells (unpublished). In addition,
FK506 reduced astrocyte proliferation and the levels of
TNFa and IL-1b mRNAs in cultured cortical astrocytes
under basal conditions (Zawadzka and Kaminska, 2005)
and impaired astrocytic hypertrophy in the cytokinecocktail-stimulated astrocytes and reduced H2O2-induced
activation of MAPK in cell culture models of astrogliosis
(Gozdz et al., unpublished). Altogether, our results demonstrate the ability of FK506 to block an early activation
of glial cells and brain inflammation, probably via interference with MAPK signaling.
Although brain inflammation and gliosis are hallmarks of brain pathology and targets of anti-inflammatory drugs, the appreciation of the beneficial side of
neuroinflammation (Schwartz et al., 2009) has initiated
the evaluation of costs and benefits of this process in
animal models of neurological disorders. Recent studies
using animals with genetic or pharmacological inactivation of microglia/macrophages point to a critical role of
the timing and the extent of microglia activation, distinct roles of different populations (resident versus CNSinfiltrating macrophages) at different time points following injury. The in vivo function of microglia and the
extent of contribution to the onset, progression, and recovery from chronic inflammation-linked disorders are
still a matter of debate, partly due to the contrasting
results derived from the different models used to assess
microglial function (Carson et al., 2008). Resident microglial cells are involved in the removal of damaged,
unwanted cells and participate in repair processes, so
the extent of inflammatory microglia activation would
determine whether detrimental effects outweigh neuroprotective mechanisms. Understanding of signaling
pathways underlying the initiatory phase of microglia
activation, synthesis of proinflammatory cytokines and
neurotoxic molecules will facilitate fine-tuning of microglial function and development of novel diagnostic and
therapeutic approaches.
Understanding of signal transduction involved in
microglia-mediated inflammation allows the discovery of
compounds which can be useful in the therapy of neurological disorders. The inhibitors of p38 MAPK and JNK
signaling pathways are clearly attractive because they
are capable of reducing both the synthesis of proinflammatory cytokines and their intracellular signaling. Second-generation inhibitors targeting activity of p38
MAPK have been improved with respect to drug
specificity. FK506, interfering with MAPK signaling,
represents another class of promising drugs with wellknown pharmacokinetics and safety. Many of these
drugs are small molecules that can be administered
orally, and a growing number of studies demonstrate
their therapeutic benefits in animal models of neurological disorders. MAPK inhibitors may be better suited for
the treatment in acute neurological disorders, as a longterm inhibition of MAPK may impair antibactericidal
mechanisms and decrease bacterial clearance during
infection. The reported side effects of the drug did not
preclude further drug development.
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mapk, inflammation, underlying, signali, gliosis, target, therapeutic, brain, transduction
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