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Recognition of pathogen-associated molecular signatures is critically important in proper

activation of the immune system. The Toll-like receptor (TLR) signaling network is responsible
for innate immune response. In human, 10 TLRs recognize a variety of ligands from pathogens
to trigger immunological responses. ( Õ
., 1997;  Õ
., 1998;  Õ

., 1998; M Õ
., 1999; V Õ
2000; Õ
 2001) TLRs activate NK- B
and other signaling pathways, which results in the secretion of various inflammatory cytokines.

uM !M 
!

The first member of the TLR family identified was a V

 protein implicated in
dorsoventral patterning during embryonal development (| Õ
 1988).  
 were the first to realize that the intracellular domain of V

 Toll showed striking
similarities to the intracellular domain of the mammalian interleukin-1 (IL-1) receptor, and

 Õ
. demonstrated that V

 Toll was also involved in the immune response of
the adult fly. Different human homologues of V

 Toll were identified and shown to
induce activation of the transcription factor nuclear factor- B (NF- B) upon overexpression,
revealing that TLRs and IL-1 receptors trigger similar signal transduction cascades (
Õ
., 1997;  Õ
., 1998).

In 1997, ["
Õ
 discovered the first human homologue of the drosophila Toll receptor,
now known as Toll-like receptor 4. It contained the Toll-like receptor/IL-1 receptor
intracytoplastic domain (
mÕ
m), but instead of an immunoglobulin (Ig) extracellular
domain like the IL-1 receptor, it showed a structure similar to that of the fly receptor, composed
of leucine-rich repeats. This similarity represented the ancient strategy of pattern recognition
receptors conserved throughout evolution and utilized by both human beings and insects. In
1998,   Õ
. discovered by positional cloning that the  gene in the lipopolysaccharide
(LPS)-nonresponsive mouse strain CH3/HeJ encoded a murine member of the TLR family,
providing the first clue of a function as pattern recognition receptors for mammalian TLRs. Once
Toll-like receptors were discovered to recognize pathogen-associated molecular patterns, they
became the most important group of pattern recognition receptors in the innate immune system.

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The structure of the Toll-like receptor has now been well characterized and has provided useful
information about the downstream cellular signaling that occurs after ligand binding ( Õ

 1996) (Figure 2.1). Toll-like receptors are transmembrane proteins with a series of leucine-
rich repeats in the N-terminal extracellular domain and a cytoplasmic portion greatly similar in
structure to that of IL-1 receptor (D" %& ' 2000). This intracellular region is hence
referred to as the Toll-IL-1 receptor homology domain (
 Õ
., 2000). The Toll-IL-1
receptor motif is also found in a number of important adaptor proteins that recruit downstream
kinases and transcription factors, such as myeloid differentiation factor 88, Toll-IL-1 receptor
domain containing adaptor protein, and Toll-IL-1 receptor domain containing adaptor inducing
interferon-ȕ (IFN-ȕ) (Õ
 1996).

Fungi
Extracellular

Leucine
rich TLR2 TLR6
repeats
Transmembrane Domain
TIR domain
(Highly conserved
cytoplasmic domain)
Intracellular

SIGNALING PATHWAY

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It is the physical interaction between the Toll-IL-1 receptor domains of the Toll-like receptor and
the adaptor proteins that form a structural platform on which other downstream signaling
molecules dock to initiate the signaling cascade. This area is so crucial that even single point
mutations in the Toll-IL-1 receptor domain have been shown to abolish the host immune
response to pathogen-associated molecular pattern stimulation of some Toll-like receptors (
Õ
 1996).

Although the exact nature of the physical interaction between the Toll-like receptor Toll-IL-1
receptor domain and adaptor proteins has not been fully clarified, structure and function studies
have provided important information regarding the molecular basis of Toll-IL-1 receptor
signaling. A large, conserved area containing a special configuration of amino acids called the
µµBB loop¶¶ was shown to protrude away from the rest of the Toll-IL-1 receptor domain that may
mediate interactions with downstream adaptor molecules ( Õ
 2000).

Also, evidence suggests that multiple signaling pathways are dependent on common Toll-IL-1
receptor residues, and the differential outcomes of Toll-like receptor activation probably reflect
diverging signaling pathways downstream of the Toll-IL-1 receptor domain ( Õ

2003).
It is uncertain whether these structurally critical areas participate in the oligomerization of the
Toll-like receptors, in the interactions with adaptor proteins, or with the subsequently recruited
kinases. Attempts to isolate the critical amino acid residues within the Toll-IL-1 receptor domain
involved in Toll-like receptor signaling continue.

#M 
!

The toll-like receptor (TLR) signaling pathway is the front-line subsystem against invasive
microorganisms for both innate and adaptive immunity (
   m ). To
sense innumerable and various pathogenic threats, TLRs have evolved to recognize pathogen-
associated molecular patterns (PAMPs), which represent molecular features on the surface of
pathogens. The TLR gene family and their pathways have been evolutionarily well conserved in
both invertebrates and vertebrates (|   m;   Õ
m).

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Each TLR binds to a variety of PAMPs that work as molecular markers of potential pathogens
that the host shall be defended against. For example, TLR4 was found to be a receptor for
lipolysaccharide (LPS) and essential to generate responses to Gram-negative bacteria in which
LPS is a part of the outer membrane (
mÕ
m), TLR9 responds to DNA-containing
unmethylated CpG motifs (|m Õ
m ), TLR3 is activated by double-stranded RNA
(ÊmÕ
m), and bacteria flagellin activates TLR5 (|mÕ
m).

TLRs and interleukin 1 receptors (IL-1Rs) have a conserved region of amino acids, which is
known as the toll/IL-1R (TIR) domain (
m Õ
m ). Signaling of the TLR/IL-1R
superfamily is mediated through myeloid differentiation primary response gene 88 (MyD88), IL-
1R-associated kinases (IRAKs), transforming growth factor beta-activated kinase 1 (TAK1),
TAK1-binding protein 1 (TAB1), TAB2, tumor necrosis factor (TNF) receptor-associated factor
6 (TRAF6), etc. (Ê
  M
 m).

It should be mentioned that TLR1, TLR2, TLR6, TLR4, and TLR5 are located on the plasma
membrane, whereas TLR3, TLR7, and TLR9 are not located on the cell surface (Ê
 
M
 m). While ligands for each TLR and interactions downstream of receptors are now
being identified at a dramatic pace, doubt is now being cast on the global logic behind all TLR
pathways. It was argued that the TLR pathway forms an hourglass structure (Dm), but
the precise shape of the global TLR signaling network and its functional implications has not
been elucidated. Since TLRs activate innate immunity and influence the nature of adaptive
immunity (|m Õ
m ), understanding the logic behind TLR signaling is the most
important topic in immunology.m

Lipoprotein
Imidazoquinolines
Triacylated Zymosan Double stranded
ss RNA
Lipoprotein GPI Anchors RNA LPS Flagellin CpG DNA

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TLR1 TLR2 TLR2 TLR6 TLR3 TLR4 TLR5 TLR7 TLR9

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TLR1 None identified Tri-acylated LP TNF-Į Defense against Mycobacteria
Mycobacterial 19-kd LP IL-12 and other organisms
(TLR2/TLR1) expressing tri-acylated LP
TLR2 HSPgp96 PG of gram-positive TNF-Į, IL-1b Defense against various gram-
HSP60 bacteria IL-6 positive bacteria,
HSP70 Acylated Lipoprotein IL-8 Mycobacteria, Mycoplasma,
Zymosan of yeast IL-10 protozoa, and fungi
Lipoteichoic acid IL-12 Activation of respiratory burst
GPI anchors NO12 Induction of apoptosis.
(Trypanosoma cruzi) IL-4, IL-5, Mast cell activation and
Outer membrane protein IL-6, IL-13 degranulation
A (Klebsiella (mast cells)
pneumoniae)
LAM (Mycobacteria)
Mycobacterial 19-kd LP
TLR3 None identified Double-stranded RNA IFN-ȕ Antiviral defense

TLR4 HSPgp96 LPS TNF-Į, IFN-ȕ Defense against various gram-

HSP60 F protein of RSV1 IL-1, IL-6,IL-10, negative bacteria, fungi, and
HSP70 Escherichia coli P IL-13, viruses Induction of apoptosis
ȕ-defensin 2 fimbriae Macrophage
Fibrinogen Mouse mammary tumor Inflammatory
virus envelope proteins protein-1a/b
TLR5 None identified Flagellin TNF-Į,IL-1b,IL-6 Defense against flagellated
IL-10, IFN-Ȗ bacteria
DC maturation
TLR6 None identified Di-acylated LP TNF-Į Defense against bacteria,
(Mycoplasma) fungi, mycoplasma, and
Zymosan of yeast protozoa
GPI anchors (T cruzi)
TLR7 Single-stranded Midazoquinolines IFN-Į Antiviral and antitumor
RNA (influenza (Imiquimod, (plasmacytoid defense
Virus Resiquimod) Loxoribine, DCs) DC maturation
Single-stranded Bropirimine IFN-Ȗ (T cells) Activation and migration of
RNA (HIV-1) IFN-ȕ, TNF-Į, Langerhans cells from skin to
IL-1,IL-6, IL-8 IL- lymph nodes
12, IL-18 TH1 development
TLR8 Single-stranded Imidazoquinolines Similar to TLR7 Similar to TLR7
RNA (HIV-1) (Imiquimod,
Resiquimod)
TLR9 Chromatin-IgG Unmethylated Cytidine- IFN-Į Antibacterial and antiviral
complexes guanine DNA (plasmacytoid defense TH1 development
Live or inactivated DCs) B cell proliferation
Herpes simplex virus IFN-ȕ ,IFN-Ȗ (NK DC maturation
cells), IL-6,IL-12



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TLR10 None identified None identified Unknown Unknown

+(- !#.!#



To appreciate the significance of Toll-like receptors and their pivotal role in immunology, it is
helpful to review the differences between adaptive and innate immunity ( Õ
 1996). The
innate immune system is charged with curbing the proliferation of an invading pathogen during
the initial stages of an infection, before the lymphocyte expansion that characterizes the adaptive
immune response. The hallmark of the innate immune system is the rapidity with which it
responds to microbes and orchestrates the appropriate cellular response to defend the host. For
this response to occur, a foreign organism must be quickly recognized and identified as a threat.
At the heart of innate immunity is professional antigen presenting cells (APCs), such as
macrophages and dendritic cells (DCs) that provide continual surveillance of the environment
and are prepared to rapidly alert other vital components of the immune system to perilous
substances.

Instead of differentiating the countless potential microorganisms, APCs recognize patterns that
are common and indispensable among pathogen classes, termed µµpathogen-associated molecular
patterns.¶¶ A classic example of a PAMP is the lipopolysaccharide (LPS) of gram-negative (GN)
bacteria, which serves as a vital structural component of the cell wall and is found across all GN
bacterial species. The receptors that recognize PAMPs are known as pattern-recognition
receptors and are found both on cellular membranes and as circulating plasma proteins. These
receptors are germ-line encoded, that is, they rely on inherited genetic material to provide the
different receptor specificities. It is estimated that the receptors of the innate immune system
number only in the hundreds and each type of receptor is identical for each individual
×["' 2000). Thus, the recognition of molecular patterns that are vital and
common to large groups of pathogenic organisms confers an evolutionary advantage to offspring
and is an efficient use of a finite genome.

During maturation, random combinations of genetic material create an incredibly large repertoire
of receptors, endowing each lymphocyte with a unique receptor. The differences in the way the
receptors of the adaptive and innate immune response are genetically engineered are
complementary: the variability of the adaptive immune response is much more significant, on the
0

m m 
m 

m
m

order of 1018 potential lymphocyte receptors per individual, yet subsequent generations must
reinvent their own defense ( Õ
 1996). The innate immune system has a limited variety
of highly evolved receptors that have been retained through generations. Also contributing to the
complementary functions are the differences in onset of action. In the adaptive immune response,
time is required for the selected cell to clonally proliferate and mature into a fully functional
effector cell, while cells of the innate immune system are able immediately to mount an effective
immune response. Toll-like receptors represent a class of membrane bound pattern recognition
receptors that not only recognize common pathogens but also, upon ligand binding, initiate a
cascade of cellular signaling that directs the subsequent immune responses.

+(/ M
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DC maturation, which is mediated by TLR family signaling, is a critical link between innate and
adaptive immunity (" Õ
, 2004).






u+(0M
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, 2004)



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The TLR signaling through different intracellular molecules, such as MAP kinases and IțB
kinases which are conserved signaling elements for many receptors, leads to a distinct set of
proinflammatory gene expressions ([  Õ
 2007).

+(1($m M
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The signaling pathways activated by TLRs are broadly classified into MyD88-dependent and
independent pathways (M  ., 2005) as MyD88 is the universal adapter protein
-

m m 
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m

recruited by all TLRs except TLR3. The major pathways activated by TLR engagement are
passed through I B kinase (IKK), MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt
pathways. These pathways regulate the balance between cell viability and inflammation. The
signaling pathways activated by a specific TLR are largely dictated by the adapter proteins
recruited to the intracellular domain of the TLR upon ligand binding (.M, 2004).
There are currently four cytosolic adaptor proteins that are thought to play a crucial role in
specificity of individual TLR-mediated signaling pathways. Amongst them, TLR4 signaling
involves all four adapter proteins, MyD88 (myeloid differentiation primary response gene 88),
MyD88 adapter like [MAL; also known as TIRAP (TIR domain-containing adapter protein)],
TIR domain-containing adapter protein inducing IFN-m ҏ[TRIF; also known as TICAM1 (TIR
domain-containing adapter molecule 1)], and TRIF-related adapter molecule [TRAM; also
known as TICAM2 (TIR domain-containing adapter molecule 2)] (  2& ,
2004). The differential recruitment of these adapter proteins by different TLRs form the basis for
the specificity in the signaling process activated by them.

+(1($($mV !!#*  

Every TLR member differentially utilizes adapters, but MyD88 (296 amino acid protein) seems
to be the widely used adapter molecule. MyD88 harbors a TIR domain as well as a death
domain. The carboxy terminal of TIR domain interacts with the cognate domains in the
cytoplasmic tails of the TLRs, and the amino terminal death domain mediates the interaction
with the corresponding domain of interleukin 1 receptor-associated kinase 4 (IRAK4) (Î
Õ
., 1997;
 Õ
., 2002). MyD88 was originally isolated as a myeloid differentiation primary
response gene that is rapidly induced upon IL-6 stimulated differentiation of M1 myloleukemic
cells into macrophages (
 Õ
., 1990).

+(1($(+m.!V ! 

Most of the TLRs seem to be absolutely dependent on the expression of MyD88 for all of their
functions. MyD88-independent signaling events are controlled by TRIF/TRAM (for TLR4 and
TLR 2,6) and induce IRF3-dependent type I interferon production (u  Õ
., 2003;
|* Õ
., 2003;  Õ
., 2003; åÕ
., 2003).

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The next component of downstream TLR signaling is the IRAK family members. IRAKs are
important mediators in the signal transduction of the TLR family as they may act to potentiate
the downstream signaling. So far, four IRAKs have been identified, such as IRAK1, IRAK2,
IRAK4 and IRAKM. IRAK1 and IRAK4 possess intrinsic serine/threonine protein kinase
activities, whereas IRAK2 and IRAKM lack this activity, that may negatively regulate TLR
mediated signaling. IRAK1 has three TRAF6 (tumor necrosis factor receptor associated factor 6)
binding motifs to mediate the interaction with TRAF6 (å Õ
., 2002) and undergoes
autophosphorylation. IRAK4 and IRAK1 are sequentially phosphorylated and dissociated from
MyD88, which results in activation of TRAF6.

+(1(+(+M.u1 #. * #

TRAF6 belongs to an E3 ubiquitin ligase family, which facilitates the synthesis of lysine 63
linked polyubiquitin chains (, 2005). TRAF6 is the activator of canonical NF- B pathway
(|  ' 2004). TRAF6 is ubiquitinated at K63 chains and this K63
polyubiquitinated TRAF6 mediates activation of the next component in the pathway, which is
most likely to be TGF-ȕҏ activated kinase-1 (TAK1) (
 Õ
., 2004). In fact, the TAK1
associated proteins, TAB2 and TAB3, contain a domain that interacts specifically with K63-
ubiquitin chains. This model for TLR signaling predicts that the TAK1-TAB complex associates
with K63-ubiquitinated TRAF6 to activate TAK1 kinase, which then activates the IKK complex
as well as the JNK kinases.
 Õ
., 2003 reported that TRAF6 is involved in TRIF mediated
IRF3 activation and NF- B activation during TLR signaling. However, a recent paper delineated
the involvement of TRAF6 in TLR signaling, where TRAF6 is involved in MyD88 mediated
NF- B activation but not TRIF mediated NF- B activation (Õ
., 2004).

+(1(0 M!#*M


PAMPs stimulation through TLR-dependent and independent pathways converges at the

activation of transcription factors NF- B, IRF3/7/5, and/or AP-1. These transcription factors
collaborate with each other to produce a large number of cytokines, which are barely detectable

6

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m 

m
m

in resting cells. The multi-transcription factor binding sites in the promoter of a given gene lead
to this highly specific activation ([  Õ
 2007). The multistage gene regulation by
this interaction and the specific transcription factors activated is discussed below.

+(1(0($m&u D* "

The continued research on TLRs has led to the delineation of specificity in the regulation and
interaction of transcription factors upon stimulation leading to a highly specific gene expression.
NF- B is the major transcription factor, which functions on TLR signaling to control/elicit
inflammation. NF- B was first described as a B cell specific transcription factor that binds the
B site in the Ig light chain enhancer (
D , 1986). Viral promoters contain NF-
B binding sites making it advantageous for its replication. So it is not exaggerating to say that
cells which have NF- B as a sword against the viral infection turn back against to them. NF- B
has often been called a µcentral mediator of the immune response¶. MAL-MyD88 and TRAM-
TRIF pathways stimulate NF- B activation albeit with different kinetics (
 3, 2006).
NF- B activity was found to be inducible in all cell types and it is now known that members of
the NF- B/Rel family regulate many genes involved in immune and inflammatory responses
(  , 1999; |, 2004).

+(1(0(+.!$. $ 

The JNK and p38 cascades are activated first and foremost in response to inflammatory
cytokines, bacterial products, and various stress factors. Activation of TAK1 during TLR
m
signaling results in the activation of MAPKs, including JNK/p38, leading to the activation of
AP-1 (& Õ

1999; .M, 2004;
 Õ

2005), which together with
NF- B governs the production of inflammatory cytokines and chemokines (".,
2006). Activation of these JNK/p38 cascades is associated with selective activation of different
AP-1 subunits and transcription factors interacting with AP-1 ([ 
!, 2002).
This activation •
p38 is necessary for the full induction of TNF-Į ҏand IL-12 as inhibition of
p38 abrogates this biological response. All these studies together indicate that it is the differential
activation and binding of AP-1 subunits, which contribute to the inflammation.

66

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Identification of the different ligands of the Toll like receptors has allowed the study of the
cellular signaling that occurs after ligand engagement. The downstream signaling has revealed
the previously unrecognized role of the innate immune system as a regulator of the adaptive
immune response at several steps along the path from Toll-like receptor engagement to the
resultant inflammatory response. The first example of the impact of Toll-like receptors in
controlling the adaptive immune system is illustrated by the events that take place during the
physical interaction between APCs and T cells in the lymphoid organs ( Õ
 1996).

The µµ2-signal hypothesis¶¶ states that when a circulating T cell encounters a captured antigen on
the surface of an APC in the context of a major histocompatibility complex, a second co-
stimulatory signal must be seen by the T cell for it to become activated and to clonally expand.
These essential co-stimulatory molecules include B7-1 (CD80) and B7-2 (CD86) on the surfaces
of APCs that engage their cognate receptors on T cells (CD28 and CD152) at the time of antigen
presentation. Engagement of Toll-like receptors by microbial products initiates the expression of
these second signals. If this critical communication between the T cell and the APC does not
occur, the T cell will invariably meet a fate of apoptosis or permanent anergy to the antigen
stimulus. This phenomenon constitutes a valuable safety mechanism to prevent an inadvertent
expansion of a T-cell clone; it requires that a pathogen must be recognized by the Toll-like
receptors of the innate immune system before a fully developed adaptive immunologic reaction
can occur ( Õ
 1996).

Secondly, the innate immune system directs the type of adaptive immune response that is waged
against a stimulus. Naʀve T cells have the potential to differentiate toward one of the two
mutually antagonistic poles of helper T (TH) cell types termed TH1 or TH2 subsets. The principal
function of the TH1 subset is to stimulate phagocyte-mediated defense against intracellular
organisms, whereas the TH2 cells promote IgE, eosinophil, and mast-cell-mediated immune
responses against extracellular pathogens (D Õ ., 2002; M, 2003, "
, 2004). The APCs produce cytokines that instruct the expanding clone of T cells to
differentiate toward either a TH1 or a TH2 profile. It is becoming increasingly clear that the
nature of the antigen and the Toll-like receptor to which it binds can determine the specific
66

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m 

m
m

cytokine milieu that the APC will produce to influence the polarity of the TH response ( Õ

 1996).

Lastly, APCs regulate a specialized subset of T cells known as regulatory T cells. Ordinarily the
peripheral effector T cells remain in a quiescent state owing to their suppression by regulatory T
cells. This mechanism of peripheral tolerance is important in protecting the host against the
development of potentially auto reactive cells, but the presence of these regulatory cells also
means that the concomitant, bystander suppression of the T cell bearing a useful receptor specific
for the pathogen-associated molecular patterns of an invading organism could result in
detrimental consequences to the host in the setting of an infection. There is now evidence that
IL- 6 secreted from Toll-like receptor activated DCs can relieve this suppression, allowing the
activation of the antigen-specific T cell during antigen presentation (   ,
2003). Therefore, the Toll-like receptor expressing APCs not only provide the necessary co-
stimulatory signals, while presenting antigens to the naïve T cells and cytokines that instruct TH1
or TH2 differentiation but also suppress the inhibitory regulators of the T cells in the appropriate
setting, thereby permitting the mounting of an effective adaptive immune response.




u+(/M|   #*M
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2001)

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During infection, CD4+ TH cell responses polarize to become primarily TH1 or TH2. TH1 cells,
which make IFN- , are crucial for immunity to many bacterial and protozoal infections, whereas
TH2 cells, which make IL-4, IL-5, and IL-13, are important for resistance to Helminth infections.
Polarized TH1 responses are induced by dendritic cells (DCs), which respond to pathogen-
derived TLR ligands to produce IL-12 and related cytokines that are instrumental in TH1 cell
outgrowth and coordinately process and present Ag in the context of MHC class II to activate
naʀve TH cells. It has become clear recently that TLR-activated DCs generally favor the
development of TH1 responses due in large part to the fact that TLR ligation usually induces the
production of IL-12, a cytokine that plays a pivotal role in TH1 cell differentiation (D Õ .,
2002; M, 2003, "  , 2004). TLR ligands can activate dendritic
cells to provide a MyD88-dependent negative signal for TH2 cell development ([,
Õ

2005).

u&
.'
(M'((2004). Toll-like receptor signalling. Nat Rev Immunol; 4:499-511.
.'
(6M'('M((2001). Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol; 2:675-
80.
D'(('((2002). Control of adaptive immune responses by Toll-like receptors. Curr. Opin. Immunol; 14:380.
D"'.( %& '
(.( (2000). The interleukin-1 receptor/toll-like receptor superfamily: signal generators for proinflammatory interleukins
and microbial products. J Leukoc Biol; 67:508
' ((6u'(6&' 7(6&' (6'|(u(6*'(6['.(6M'D([(6|'
(& ' (
(
(1998). Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in
humans. Blood 91:4020-4027.
'8([((2005). Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol; 7:758-65
'M( 9 '([( (2001). Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells.
Biochim. Biophys. Acta 1518)157-161.
 '(6M'(
'å[((2004). Plasmacytoid dendritic cells in immunity. Nat Immunol; 5:1219-26.
V'(6  ' .(6 Î'å( D 'D( (2000). Three novel mammalian Toll-like receptors: gene structure, expression, and evolution.
Eur. Cytokine Netw. 11)362-371.
u '(.(6Î'
((6u'(
(6"'V(('
'(6 *'V(M(6 '.([(6
'
(('M((2003).
IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol; 4:491-6.
u ' (.(6  V' ((6 D" .' [## .'   .
' D ' D ' V .'  ' | M'
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 V'
 [' D M.  2& 
.( (2001). Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal
transduction. Nature; 413:78-83.
'&([('u([( (1991). V

 Toll and IL-1 receptor. Nature 351)355-356.
 '(8( (2006). "Integrin signaling in epithelial cells". „Õ
Õ  247 (1): 1-25.
'[(6'M(6'[( (2004). Cutting edge: TNFRassociated factor (TRAF) 6 is essential for MyD88-dependent pathway but
not toll/IL-1 receptor domaincontaining adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol; 173:2913-7
|' (6 |' (
(  .' ( 7( 1988). The Toll gene of V

, required for dorsal-ventral embryonic polarity,
appears to encode a transmembrane protein. Cell 52:269-279.
|'(
(6'
( (2004) Signaling to NF-kappaB. Genes Dev; 18:2195-224.

6Œ

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( (6'[(6
' (6'&(6'
(6'(6
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