El lenguaje del sistema inmune: las citoquinas

Inmunologa Bsica
Mayo, 2012
Persio D. Lpez Loyo
Friday, May11, 12
Las ci toqui nas son prote nas o
gl i coprote nas de baj o peso
mol ecul ar que son secretadas por
di ferentes cl ul as del cuerpo y, en
parti cul ar, del si stema i nmune, con
el fi n de regul ar y di ri gi r el desarrol l o
y l a funci n de l as cl ul as efectoras
del si stema i nmune.
Friday, May11, 12
Kindt TJ, Goldsby RA,
Osborne BA, Kuby J.
Kuby immunology. 6th
ed. New York: W. H.
Freeman; 2007. Figure
12.2, Cytokine atributes
o r p l e i o t r o p y ,
redundancy, synergy
(synergism), antagonism
and cascade induction;
p. 278.
immune-system cells. Soon after, it was discovered that pro-
duction of these factors by cultured lymphocytes was induced
by activation with antigen or with nonspecific mitogens. Bio-
chemical isolation and purification of cytokines was ham-
pered because of their low concentration in culture super-
natants and the absence of well-defined assay systems for
individual cytokines. A great advance was made with the
development of gene-cloning techniques during the 1970s
and 1980s, which made it possible to produce pure cytokines
by expressing the protein from cloned genes. The discovery of
278 PART I I I Immune Effector Mechanisms
Activated T
H
cells
PLEIOTROPY
Mast cell
IL-4
Thymocyte
B cell
Activation
Proliferation
Differentiation
Proliferation
Target Cell Effect
IL- 4
Proliferation
IL-2
IL-5
Activated T
H
cells
REDUNDANCY
IL- 4
+
IL-5
Activated T
H
cells
SYNERGY
Induces class switch to IgE
Blocks class switch to IgE
induced by IL- 4
IL- 4
IFN-
Activated T
H
cells
ANTAGONISM
Proliferation
B cell
B cell
B cell
Activated T
H
cells
Activated T
H
cells
IFN-, TNF, IL-2, and
other cytokines
Macrophage
IL-12
CASCADE INDUCTION
IFN-
(a) (b)
FI GURE 12-2 Cytokine attributes of (a) pleiotropy, redundancy,
synergy (synergism), antagonism, and (b) cascade induction.
Friday, May11, 12
Un close-up: caractersticas y clasicacin
Friday, May11, 12
La familia de las
citoquinas tipo I
Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure
23.1, Schematic of four -helical-bundle cytokines; p. 708.
Friday, May11, 12
La familia de las
citoquinas tipo I
Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure
23.1, Schematic of four -helical-bundle cytokines; p. 708.
15 aa
25 aa
Friday, May11, 12
La familia de las
citoquinas tipo I
Interleucina (IL)-2 GH
IL-3 Prolactina
IL-4 Eritropoyetina
IL-5 Trombopoyetina
GM-CSF Leptina
IL-7 IL-6
IL-9 IL-11
IL-13 Factor inhibidor de leucemia (LIF)
IL-15 Oncostatina M (OSM)
IL-21 otras
M-CSF
SCF
TSLP
Friday, May11, 12
La familia de las
citoquinas tipo II
Friday, May11, 12
La familia de las
citoquinas tipo II
Interfern (IFN)-
IFN-
IFN-
IL-10
IL-19
IL-20
IL-22
IL-24
IL-26
IL-28
IL-29
Friday, May11, 12
La familia de IL-1
Friday, May11, 12
La familia de IL-1
IL-1
IL-1
IL-1Ra
IL-18
IL-33
otros
Friday, May11, 12
La familia del factor de
necrosis tumoral (TNF)
Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure
25.1, Structure of Tumor Necrosis Factor (TNF); p. 780.
Friday, May11, 12
La familia del factor de
necrosis tumoral (TNF)
15-20 aa
Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure
25.1, Structure of Tumor Necrosis Factor (TNF); p. 780.
150 aa
Friday, May11, 12
La familia del factor de
necrosis tumoral (TNF)
Factor de Necrosis Tumoral (TNF)
Linfotoxina A
Linfotoxina B
TNFS4-15,18
EDA
otros
4
0
+

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i
g
a
n
d
o
s
,

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a
d
a

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n
o

c
o
n

s
u

r
e
c
e
p
t
o
r

p
r
o
p
i
o
Friday, May11, 12
Cmo funcionan estas molculas?
Friday, May11, 12
Familia de receptores
citoqunicos clase I
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby
immunology. 6th ed. New York: W.H. Freeman; 2007. Figure
12.6b, Schematic diagrams showing the structural features
that dene the ve types of receptor proteins to which most
cytokines bind; p. 282.
Cytokine Receptors
As noted already, to exert their biological effects, cytokines
must first bind to specific receptors expressed on the mem-
brane of responsive target cells. Because these receptors are
expressed by many types of cells, the cytokines can affect a
diverse array of cells. Biochemical characterization of cyto-
kine receptors initially progressed at a very slow pace because
their levels on the membrane of responsive cells is quite low.
As with the cytokines themselves, cloning of the genes encod-
ing cytokine receptors has led to rapid advances in the iden-
tification and characterization of these receptors.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse struc-
turally, but almost all belong to one of five families of recep-
tor proteins (Figure 12-6):

Immunoglobulin superfamily receptors

Class I cytokine receptor family (also known as the

hematopoietin receptor family)

Class II cytokine receptor family (also known as the

interferon receptor family)

TNF receptor family

Chemokine receptor family

Many of the cytokine-binding receptors that function in
the immune and hematopoietic systems belong to the class I
cytokine receptor family. The members of this receptor family
have conserved amino acid sequence motifs in the extracellu-
lar domain consisting of four positionally conserved cysteine
residues (CCCC) and a conserved sequence of tryptophan-
serine-(any amino acid)-tryptophan-serine (WSXWS, where
X is the nonconserved amino acid). The receptors for all the
cytokines classified as hematopoietins belong to the class I
cytokine receptor family, which also is called the hematopoi-
etin receptor family. The class II cytokine receptors possess
the conserved CCCC motifs, but lack the WSXWS motif pre-
sent in class I cytokine receptors. Initially only the three
interferons, , , and , were thought to be ligands for these
receptors. However, recent work has shown that the IL-10
receptor is also a member of this group.
Another feature common to most of the hematopoietin
(class I cytokine) and the class II cytokine receptor families is
282 PART I I I Immune Effector Mechanisms
RECEPTOR FAMILY LIGANDS
(a) Immunoglobulin superfamily
receptors
IL-1
M-CSF
C-Kit
S
S
S
S
S
S
(b) Class I cytokine receptors
(hematopoietin)
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9
IL-11
IL-12
IL-13
IL-15
GM-CSF
G-CSF
OSM
LIF
CNTF
Growth hormone
Prolactin
Conserved
cysteines
WSXWS
(c) Class II cytokine receptors
(interferon)
IFN-
IFN-
IFN-
IL-10
C
C
C
C
(d) TNF receptors
C1
C3
C2
C1
C3
C2
C1
C3
C2
C1
C3
C2
TNF-
TNF-
CD40
Nerve growth factor (NGF)
FAS
(e) Chemokine receptors
IL-8
RANTES
MIP-1
PF4
MCAF
NAP-2
G-protein
FIGURE 12-6 Schematic diagrams showing the structural features
that define the five types of receptor proteins to which most cytokines
bind. The receptors for most of the interleukins belong to the class I
cytokine receptor family. C refers to conserved cysteine.
Friday, May11, 12
Familia de receptores
citoqunicos clase I
Abbas AK, Lichtman AH. Cellular and molecular immunology.
5th ed. Philadelphia, PA: Saunders; 2005. Figure 11.3b,
Structure of cytokine receptors; p. 248.
IL-2, IL-4, IL-7,
IL-9, IL-15, IL-21
IL-3, IL-5,
GM-CSF
IL-6, IL-11,
LIF, OSM,
CNTF, CT-1,
CLC, IL-27
Friday, May11, 12
Familia de receptores
citoqunicos clase II
Cytokine Receptors
As noted already, to exert their biological effects, cytokines
must first bind to specific receptors expressed on the mem-
brane of responsive target cells. Because these receptors are
expressed by many types of cells, the cytokines can affect a
diverse array of cells. Biochemical characterization of cyto-
kine receptors initially progressed at a very slow pace because
their levels on the membrane of responsive cells is quite low.
As with the cytokines themselves, cloning of the genes encod-
ing cytokine receptors has led to rapid advances in the iden-
tification and characterization of these receptors.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse struc-
turally, but almost all belong to one of five families of recep-
tor proteins (Figure 12-6):

Immunoglobulin superfamily receptors

Class I cytokine receptor family (also known as the

hematopoietin receptor family)

Class II cytokine receptor family (also known as the

interferon receptor family)

TNF receptor family

Chemokine receptor family

Many of the cytokine-binding receptors that function in
the immune and hematopoietic systems belong to the class I
cytokine receptor family. The members of this receptor family
have conserved amino acid sequence motifs in the extracellu-
lar domain consisting of four positionally conserved cysteine
residues (CCCC) and a conserved sequence of tryptophan-
serine-(any amino acid)-tryptophan-serine (WSXWS, where
X is the nonconserved amino acid). The receptors for all the
cytokines classified as hematopoietins belong to the class I
cytokine receptor family, which also is called the hematopoi-
etin receptor family. The class II cytokine receptors possess
the conserved CCCC motifs, but lack the WSXWS motif pre-
sent in class I cytokine receptors. Initially only the three
interferons, , , and , were thought to be ligands for these
receptors. However, recent work has shown that the IL-10
receptor is also a member of this group.
Another feature common to most of the hematopoietin
(class I cytokine) and the class II cytokine receptor families is
282 PART I I I Immune Effector Mechanisms
RECEPTOR FAMILY LIGANDS
(a) Immunoglobulin superfamily
receptors
IL-1
M-CSF
C-Kit
S
S
S
S
S
S
(b) Class I cytokine receptors
(hematopoietin)
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9
IL-11
IL-12
IL-13
IL-15
GM-CSF
G-CSF
OSM
LIF
CNTF
Growth hormone
Prolactin
Conserved
cysteines
WSXWS
(c) Class II cytokine receptors
(interferon)
IFN-
IFN-
IFN-
IL-10
C
C
C
C
(d) TNF receptors
C1
C3
C2
C1
C3
C2
C1
C3
C2
C1
C3
C2
TNF-
TNF-
CD40
Nerve growth factor (NGF)
FAS
(e) Chemokine receptors
IL-8
RANTES
MIP-1
PF4
MCAF
NAP-2
G-protein
FIGURE 12-6 Schematic diagrams showing the structural features
that define the five types of receptor proteins to which most cytokines
bind. The receptors for most of the interleukins belong to the class I
cytokine receptor family. C refers to conserved cysteine.
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby
immunology. 6th ed. New York: W.H. Freeman; 2007. Figure
12.6c, Schematic diagrams showing the structural features
that dene the ve types of receptor proteins to which most
cytokines bind; p. 282.
Friday, May11, 12
Kindt TJ, Goldsby RA, Osborne BA, Kuby J.
Kuby immunology. 6th ed. New York: W.H.
Freeman; 2007. Figure 12.10, General model of
signal transduction mediated by most class I and
class II receptors; p. 286.
complex. Members of a family of transcription factors
known as STATs (signal transducers and activators of
transcription) bind to these phosphorylated tyrosine
residues. Specific STATs (see Table 12-2) play essential
roles in the signaling pathways of a wide variety of
cytokines. The binding of STATs to receptor subunits is
mediated by the joining of the SH2 domain on the
STAT with the docking site created by the JAK-mediated
phosphorylation of a particular tyrosine on receptor
subunits.

After undergoing JAK-mediated phosphorylation, STAT

transcription factors translocate from receptor docking
sites at the membrane to the nucleus, where they initiate
the transcription of specific genes. While docked to
receptor subunits, STATs undergo JAK-catalyzed
phosphorylation of a key tyrosine. This is followed by
the dissociation of the STATs from the receptor subunits
and their dimerization. The STAT dimers then
translocate into the nucleus and induce the expression
of genes containing appropriate regulatory sequences in
their promoter regions.
In addition to IFN-, a number of other class I and class II
ligands have been shown to cause dimerization of their re-
ceptors. An important element of cytokine specificity derives
from the exquisite specificity of the match between cytokines
and their receptors. Another aspect of cytokine specificity is
that each particular cytokine (or group of redundant cyto-
kines) induces transcription of a specific subset of genes in a
given cell type; the resulting gene products then mediate the
various effects typical of that cytokine. The specificity of
cytokine effects is then traceable to three factors. First, par-
ticular cytokine receptors start particular JAK-STAT path-
ways. Second, the transcriptional activity of activated STATs
286 PART I I I Immune Effector Mechanisms

Dimerization
of receptor
Activation of JAK
family tyrosine kinases,
phosphorylation of receptor
Tyrosine phosphorylation of
STAT by JAK kinase
Dimerization
of STAT
DNA
Specific gene transcription
P
P
P P
P P
P
P
P
P
STAT
SH
2
JAK
Cytokine
FIGURE 12-10 General model of signal transduction mediated by
most class I and class II cytokine receptors. Binding of a cytokine in-
duces dimerization of the receptor subunits, which leads to the activa-
tion of receptor-subunit-associated JAK tyrosine kinases by reciprocal
phosphorylation. Subsequently, the activated JAKs phosphorylate vari-
ous tyrosine residues, resulting in the creation of docking sites for
STATs on the receptor and the activation of the one or more STAT tran-
scription factors. The phosphorylated STATs dimerize and translocate
to the nucleus, where they activate transcription of specific genes.
FIGURE 12-11 The complex between IFN- and the ligand-binding
chains of its receptor. This model is based on the x-ray crystallo-
graphic analysis of a crystalline complex of interferon- (violet and
blue) bound to ligand-binding chains of the receptor (green and
yellow). Note that IFN- is shown in its native dimeric form; each
member of the dimer engages the chain of an IFN- receptor,
thereby bringing about receptor dimerization and signal transduc-
tion. [From M. R. Walter et al., 1995, Nature 376:230, courtesy M. Walter,
University of Alabama.]
Friday, May11, 12
Paul WE. Fundamental Immunology. 6th ed.
Philadelphia: Wolters Kluwer/Lippincott Williams
& Wilkins; 2008. Figure 23.7, Schematic of
cytokine signaling showing multiple signaling
pathways activated by IL-2; p. 733.
Friday, May11, 12
Receptores de la
superfamilia de las Igs
Cytokine Receptors
As noted already, to exert their biological effects, cytokines
must first bind to specific receptors expressed on the mem-
brane of responsive target cells. Because these receptors are
expressed by many types of cells, the cytokines can affect a
diverse array of cells. Biochemical characterization of cyto-
kine receptors initially progressed at a very slow pace because
their levels on the membrane of responsive cells is quite low.
As with the cytokines themselves, cloning of the genes encod-
ing cytokine receptors has led to rapid advances in the iden-
tification and characterization of these receptors.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse struc-
turally, but almost all belong to one of five families of recep-
tor proteins (Figure 12-6):

Immunoglobulin superfamily receptors

Class I cytokine receptor family (also known as the

hematopoietin receptor family)

Class II cytokine receptor family (also known as the

interferon receptor family)

TNF receptor family

Chemokine receptor family

Many of the cytokine-binding receptors that function in
the immune and hematopoietic systems belong to the class I
cytokine receptor family. The members of this receptor family
have conserved amino acid sequence motifs in the extracellu-
lar domain consisting of four positionally conserved cysteine
residues (CCCC) and a conserved sequence of tryptophan-
serine-(any amino acid)-tryptophan-serine (WSXWS, where
X is the nonconserved amino acid). The receptors for all the
cytokines classified as hematopoietins belong to the class I
cytokine receptor family, which also is called the hematopoi-
etin receptor family. The class II cytokine receptors possess
the conserved CCCC motifs, but lack the WSXWS motif pre-
sent in class I cytokine receptors. Initially only the three
interferons, , , and , were thought to be ligands for these
receptors. However, recent work has shown that the IL-10
receptor is also a member of this group.
Another feature common to most of the hematopoietin
(class I cytokine) and the class II cytokine receptor families is
282 PART I I I Immune Effector Mechanisms
RECEPTOR FAMILY LIGANDS
(a) Immunoglobulin superfamily
receptors
IL-1
M-CSF
C-Kit
S
S
S
S
S
S
(b) Class I cytokine receptors
(hematopoietin)
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9
IL-11
IL-12
IL-13
IL-15
GM-CSF
G-CSF
OSM
LIF
CNTF
Growth hormone
Prolactin
Conserved
cysteines
WSXWS
(c) Class II cytokine receptors
(interferon)
IFN-
IFN-
IFN-
IL-10
C
C
C
C
(d) TNF receptors
C1
C3
C2
C1
C3
C2
C1
C3
C2
C1
C3
C2
TNF-
TNF-
CD40
Nerve growth factor (NGF)
FAS
(e) Chemokine receptors
IL-8
RANTES
MIP-1
PF4
MCAF
NAP-2
G-protein
FIGURE 12-6 Schematic diagrams showing the structural features
that define the five types of receptor proteins to which most cytokines
bind. The receptors for most of the interleukins belong to the class I
cytokine receptor family. C refers to conserved cysteine.
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby
immunology. 6th ed. New York: W.H. Freeman; 2007. Figure
12.6a, Schematic diagrams showing the structural features
that dene the ve types of receptor proteins to which most
cytokines bind; p. 282.
Friday, May11, 12
Receptores de la
superfamilia de las Igs
2005 Nature Publishing Group

Plasma
membrane
SIGIRR
NF-B
ST2 IL-1RRP2 IL-1R2
?
IL-1
IL-1
IL-1RA
IL-1
IL-1
IL-1RA
IL-1F7
IL-18
? ? ?
IL-1F5
IL-1F6
IL-1F8
IL-1F9
NF-B
MAPKs
No signal NF-B
MAPKs
NF-B
MAPKs
IL-1R
signalling
? ? MAPKs
IL-1R1 IL-1RAcP IL-18RAcP TIGIRR IL-1RAPL1 IL-18R IL-1RAcP
CALPAIN
One of a group of calcium-
activated cytoplasmic proteases
that are found in many tissues
and that hydrolyse various
endogenous proteins, including
neuropeptides and cytoskeletal
proteins, as well as proteins
from smooth muscle, cardiac
muscle, liver, platelets and
erythrocytes. Two subclasses
are known: one with high
calcium sensitivity, and one
with low calcium sensitivity.
CASPASE
One of a group of enzymes
that have a role in promoting
apoptosis (that is, programmed
cell death). Inhibition of such
enzymes might be useful for
combating cell and tissue
damage in conditions such as
myocardial infarction, stroke,
inflammatory diseases and
neurodegenerative disease.
Augmentation of such enzymes,
through the production of
pro-apoptotic proteins, might
be useful for combating
proliferative conditions, such
as cancer.
DECOY RECEPTOR
A receptor that can bind a
ligand and thereby prevent
the ligand from associating
with the conventional signalling
receptor.
TOLL/IL1 RECEPTOR DOMAIN
(Toll/interleukin-1-receptor
domain; TIR domain). An
intracellular-signalling domain
that is found in IL-1 receptors,
Toll-like receptors and several
adaptor proteins, including
MyD88 (myeloid differentiation
primary-response protein 88).
ISCHAEMIC INJURY
Damage to neurons that results
from a deficiency in blood
supply to that region of the
brain, owing to functional
constriction or physical
obstruction of a blood vessel.
of the promoter for initiating transcription. There are
also several binding regions for tissue-specific factors,
including nuclear factor-A (NF-A) and SP1, and these
determine cell-type-specific expression. Transcription of
the genes that encode IL-1 is also affected by numerous
factors that recognize and bind DNA regulatory sites,
such as the cyclic AMP response element, the activa-
tor protein 1 (AP1)- and NF-B-binding site, and the
lipopolysaccharide (LPS)-response enhancer site
14
. As
well as these, several other signals (both intracellular
and extracellular) can function to increase the rate of
transcription of the gene encoding IL-1, including
complement components and prostaglandin E
2
(PGE
2
).
However, perhaps most relevant to CNS injury are the
-chain of the S100 calcium-binding protein (S100B;
also known as neurite extension factor), -amyloid
(which is present in plaques in Alzheimers disease)
and excitotoxins (excitatory amino-acid-receptor
agonists), all of which clearly have prominent roles
in the brain
17,18
. Other factors function to inhibit
the transcription of genes encoding IL-1, including
glucocorticoids and their anti-inflammatory media-
tor annexin-1 (also known as lipocortin-1), which is
neuroprotective against ISCHAEMIC INJURY
19
.
Post-transcriptional and translational regulation.
Production of the inactive pro-IL-1 protein can be
regulated in several ways (both positively and nega-
tively), and in many situations, this is dissociated from
changes in expression of mRNA encoding IL-1
14
. For
example, LPS can increase IL-1 protein production
through increasing mRNA stability
20
. Translation can
also be increased by epidermal growth factor, cortico-
tropin-releasing hormone and ICAM1, whereas
translation is inhibited by dexamethasone (a synthetic
glucocorticoid)
14
.
Post-translational and cellular-release regulation.
Cellular release of IL-1 seems to require two
stimuli
21,22
. For example, treatment of macrophages
or microglial cells with LPS induces expression of
pro-IL-1 but not cleavage or release. Subsequent
activation of P2X7 a purinergic receptor and
ligand-gated ion channel by ATP (or ADP), in LPS-
primed macrophages, elicits both cleavage of mature
IL-1 through a caspase-1-dependent process and its
subsequent release
23
. This process of IL-1 release
depends on the release of calcium from intracellular
stores and on the activation of phospholipase C and
phospholipase A
2
REFS 24,25.
As well as ATP, other stimuli can also provide the
second signal that leads to IL-1 cleavage and release,
and these stimuli have in common the ability to pro-
duce marked changes in the ionic composition of the
cell that is releasing IL-1. Consistent with this, acti-
vation of the receptor P2X7 leads to potassium efflux
and therefore to a decline in intracellular potassium
concentration, which seems to be essential for the
activation of caspase-1 REFS 22,26,27. However, there
has been much debate about the physiological rel-
evance of ATP as a regulator of IL-1 release, because
ATP, and other release-inducing stimuli, result in
death of the IL-1-producing cell. Recent work has
identified LL37 (also known as CAMP) an anti-
microbial peptide to be an inducer of IL-1 release
through activation of P2X7 REF. 28. By contrast, a
novel family of cytokine-release inhibitory drugs
(CRIDs) block IL-1 release in response to diverse
stimuli (that is, LPS and ATP, hypotonic stress, and
cytotoxic T lymphocytes), but they do not function
through P2X7 REF. 29. One of the main targets of
CRIDs is the enzyme glutathione S-transferase-1-1
(GSTO1), which might be a crucial regulator of
Figure 1 | The interleukin-1 family. The various members of the interleukin-1 (IL-1) family and their receptors are shown.
Possible receptorligand interactions that initiate downstream signalling are also indicated. IL-1F, IL-1 family; IL-1R1, type I IL-1
receptor; IL-1R2, type II IL-1 receptor; IL-1RA, IL-1-receptor antagonist; IL-1RAcP, IL-1-receptor accessory protein;
IL-1RAPL1, IL-1-receptor accessory-protein-like 1; IL-1RRP2, IL-1-receptor-related protein 2; IL-18R, IL-18 receptor;
IL-18RAcP, IL-18-receptor accessory protein; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor-B;
SIGIRR, single immunoglobulin IL-1-receptor-related molecule; TIGIRR, three-immunoglobulin-domain-containing IL-1-receptor-
related molecule.
NATURE REVIEWS | IMMUNOLOGY VOLUME 5 | AUGUST 2005 | 631
R E V I E WS
Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal
injury. Nat Rev Immunol. 2005 Aug.;5(8):629640. Figure 1,
The interleukin-1 family; p. 631.
Friday, May11, 12
Familia del receptor de
TNF
Cytokine Receptors
As noted already, to exert their biological effects, cytokines
must first bind to specific receptors expressed on the mem-
brane of responsive target cells. Because these receptors are
expressed by many types of cells, the cytokines can affect a
diverse array of cells. Biochemical characterization of cyto-
kine receptors initially progressed at a very slow pace because
their levels on the membrane of responsive cells is quite low.
As with the cytokines themselves, cloning of the genes encod-
ing cytokine receptors has led to rapid advances in the iden-
tification and characterization of these receptors.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse struc-
turally, but almost all belong to one of five families of recep-
tor proteins (Figure 12-6):

Immunoglobulin superfamily receptors

Class I cytokine receptor family (also known as the

hematopoietin receptor family)

Class II cytokine receptor family (also known as the

interferon receptor family)

TNF receptor family

Chemokine receptor family

Many of the cytokine-binding receptors that function in
the immune and hematopoietic systems belong to the class I
cytokine receptor family. The members of this receptor family
have conserved amino acid sequence motifs in the extracellu-
lar domain consisting of four positionally conserved cysteine
residues (CCCC) and a conserved sequence of tryptophan-
serine-(any amino acid)-tryptophan-serine (WSXWS, where
X is the nonconserved amino acid). The receptors for all the
cytokines classified as hematopoietins belong to the class I
cytokine receptor family, which also is called the hematopoi-
etin receptor family. The class II cytokine receptors possess
the conserved CCCC motifs, but lack the WSXWS motif pre-
sent in class I cytokine receptors. Initially only the three
interferons, , , and , were thought to be ligands for these
receptors. However, recent work has shown that the IL-10
receptor is also a member of this group.
Another feature common to most of the hematopoietin
(class I cytokine) and the class II cytokine receptor families is
282 PART I I I Immune Effector Mechanisms
RECEPTOR FAMILY LIGANDS
(a) Immunoglobulin superfamily
receptors
IL-1
M-CSF
C-Kit
S
S
S
S
S
S
(b) Class I cytokine receptors
(hematopoietin)
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9
IL-11
IL-12
IL-13
IL-15
GM-CSF
G-CSF
OSM
LIF
CNTF
Growth hormone
Prolactin
Conserved
cysteines
WSXWS
(c) Class II cytokine receptors
(interferon)
IFN-
IFN-
IFN-
IL-10
C
C
C
C
(d) TNF receptors
C1
C3
C2
C1
C3
C2
C1
C3
C2
C1
C3
C2
TNF-
TNF-
CD40
Nerve growth factor (NGF)
FAS
(e) Chemokine receptors
IL-8
RANTES
MIP-1
PF4
MCAF
NAP-2
G-protein
FIGURE 12-6 Schematic diagrams showing the structural features
that define the five types of receptor proteins to which most cytokines
bind. The receptors for most of the interleukins belong to the class I
cytokine receptor family. C refers to conserved cysteine.
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby
immunology. 6th ed. New York: W.H. Freeman; 2007. Figure
12.6d, Schematic diagrams showing the structural features
that dene the ve types of receptor proteins to which most
cytokines bind; p. 282.
Friday, May11, 12
Familia del receptor de
TNF
Aggarwal BB. Signalling pathways of the TNF superfamily: a
double-edged sword. Nat Rev Immunol. 2003 Sep.;3(9):745
756. Figure 2, Cellular signaling pathways leading to
activation of the main cellular responses by members of the
TNF superfamily; p. 749.
Friday, May11, 12
ProteinLounge. TNF Superfamily Pathway.
San Diego: ProteinLounge; 2012. Available
at: http://proteinlounge.com/Pathway/TNF
%20Superfamily%20Pathway
Friday, May11, 12
Ejemplos generales del papel de las citoquinas
Friday, May11, 12
Inamacin
aguda
Inamacin
crnica
IL-8
IL-16
G-CSF
IL-1
IL-11
TNF-
IL-6
IL-17
Eotaxina
GM-CSF
IL-2
IL-4
IFNs
IL-3
IL-5
TGF-
TNF-
IL-7
IL-9
IL-10
IL-12
IL-13
IL-14
IL-15
Friday, May11, 12
Antigens
Bacteria Fungi
Protozoans
(e.g. helminths) Pollen
Genetic susceptibility (e.g. MHC, TCR etc.)
Macrophage
NK cell !/" T cell Basophils,
mast cell
IL-12
IFN-!
IL-4
?
Cytokine milieu
TCR MHC II
B7-1
CD28
T
H
0
Dendritic
cell
T
H
2 T
H
1
IFN-!
IL-10
IL-4
Intracellular
killing
B cell
Antibody
Macro-
phage
A. Differentiation into T
H
1 and T
H
2 cells
B. Regulation of IgE production
IL-4
IL-13
IL-4R
Ag
sIgM
TCR
CD40
ligand
IgE
T
H
2 B cell
IL-12 IFN-! IL-4
MHC II
CD28
TCR
B7-1
Dendritic
cell
IL-4
I
L
-
1
0
I
L
-
4
MHC + Ag
IL-4
IL-4R IL-4R
CD40
(CD80) (CD80)
IL-2
IFN-!
TNF-#
IL-5
I
F
N
-
!
T
H
1 and T
H
2 Cells
"
3
"
F
u
n
d
a
m
e
n
t
a
l
P
r
i
n
c
i
p
l
e
s
21
3
Burmester, Color Atlas of Immunology 2003 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Burmester G-R, Pezzutto A, Ulrichs T, Aicher A. Color atlas of immunology. Stuttgart; New
York: Thieme; 2003. Figure 10a, Differentiation into Th1 and Th2 cells; p. 21.
Friday, May11, 12
Lin W-W, Karin M. A cytokine-mediated link between innate immunity, inammation, and
cancer. Journal of Clinical Investigation. 2007 May;117(5):11751183. Figure 1.
review series
1176 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 5 May 2007
(PAMPs), such as cell wall components and nucleic acids (23). At
least four families of mammalian innate immune receptors that
recognize PAMPs have been identified; these are known as pattern
recognition receptors (PRRs) and include TLRs, nucleotide-bind-
ing oligomerization domainlike (NOD-like) receptors (NLRs),
C-type lectin receptors (CLRs), and triggering receptors expressed
on myeloid cells (TREMs) (2427). The interaction between PAMPs
and PRRs results in the activation of inflammatory cells and ini-
tiation of host responses whose major purpose is to eliminate
and kill invading organisms (9). However, inadequate pathogen
eradication, prolonged inflammatory signaling, and defects in anti-
inflammatory mechanisms can all lead to chronic inflammation
and benefit tumor development (28).
In addition to epidemiological data linking chronic infections to
increased cancer risk (2, 3, 29), genetic links between PRRs and can-
cer also exist. Polymorphisms in a gene cluster encoding TLR6 and
TLR10 have been linked to an increased risk of prostate cancer (30),
and mutations in the NOD2 locus have been linked to an increased
risk for developing Crohn disease (31), an IBD associated with a
modestly increased risk of developing colorectal cancer (32). These
mutations in NOD2 have been suggested to provide a gain-of-func-
tion that results in increased IL-1 production, which makes the
environment more proinflammatory (33). Interestingly, polymor-
phisms in the promoter region of the gene encoding IL-1 and the
gene encoding the IL-1 receptor antagonist (IL-1RA) have also been
linked to an increased risk of developing cancer, in particular gas-
tric cancer (34, 35). IL-1 is abundant at tumor sites, where it can
stimulate the growth and invasiveness of malignant cells (36). Inhi-
bition of IL-1 function using the naturally occurring inhibitor of
IL-1, IL-1RA, might be useful for the treatment of cancer (37).
Activation of TLR signaling can enhance tumor development
through various mechanisms. In a mouse model of transplanted
metastatic cancers, activation of TLR4 by intraperitoneal injec-
tion of bacterial LPS stimulated the growth of lung metastases
(21, 38, 39). TLR4 activation of host macrophages resulted in
the production of several different inflammatory cytokines that
influenced tumor growth. TNF- was identified as the major
host-produced factor that enhances the growth of lung metasta-
ses in this mouse model, in part through activation of NF-B in
the tumor cells (39). However, TLR4 signaling also induced the
production of IFNs, cytokines that have antitumor effects (39).
In this particular case, IFNs were found to stimulate production
of the TNF superfamily member TNF-related apoptosis-induc-
ing ligand (TRAIL) (39). TRAIL is a potent inducer of tumor cell
death (40), but in this mouse model of transplanted metastatic
cancer, its tumoricidal activity was evident only upon inhibition
of NF-B activity in the tumor cells (39). These results illustrate
that activation of innate immunity results in the production of
different cytokines with opposing activities (Figure 2) TNF-
stimulated tumor cell growth and survival, whereas TRAIL
induced tumor cell death, leading to tumor regression. However,
only by inhibiting NF-B activation in the tumor cells was the
balance shifted from stimulation of tumor growth by TNF- to
enhanced tumor cell killing by TRAIL (39).
TLR expression and function are not restricted to innate
immune cells and can directly affect the tumor cell. For example,
multiple myeloma (MM) cells frequently express multiple TLRs
and can thereby sense the presence of microorganisms (41, 42).
Indeed, ligands for both TLR7 and TLR9 have been shown to
stimulate the growth of MM cells and to protect these cells from
Figure 1
The diagram shows two outcomes of inter-
actions between tumor cells and infiltrating
inflammatory and/or immune cells in the
tumor microenvironment. Cytokines secret-
ed by tumor and inflammatory/immune cells
can either promote tumor development and
tumor cell survival or exert antitumor effects.
Chronic inflammation develops through the
action of various inflammatory mediators,
including TNF-, L-6, and L-17, leading to
eradication of antitumor immunity and accel-
erated tumor progression. However, TRAL,
through direct induction of tumor cell apopto-
sis, L-10, through antiinflammatory effects,
and L-12, through activation of CTLs and NK
cells and expression of cytotoxic mediators,
can lead to tumor suppression. The multiple
actions of TGF- (cytotoxic in colon cancer
cells, and having both positive and negative
effects on the tumor microenvironment) and
L-23 (see Figure 3) explain their dual roles
in tumor development.
Friday, May11, 12
Next class: Sistema inmune innato humoral
Paul WE. Fundamental Immunology. 6th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008.
Captulo 33
Roitt IM, Brostoff J, Male DK. Immunology. 7th ed. Edinburgh ; New York: Mosby; 2009.
Captulo 4
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby immunology. 6th ed. New York: W.H. Freeman; 2007.
Captulo 13
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