IL-6 Ligand and Receptor Family

14 Pages·0.172 MB·English

by  Hirano T., Fukada T.

IL-6 Ligand and
Receptor Family
Toshio Hirano* and Toshiyuki Fukada
Division of Molecular Oncology, Department of Oncology, Biomedical Research Center,
Osaka University Graduate School of Medicine (C7), 2-2, Yamada-oka, Suita, Osaka, 565, Japan
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.02007.
SUMMARY INTRODUCTION
The interleukin-6 (IL-6) family of cytokines is com- The IL-6 family of cytokines is composed of IL-6,
posedofIL-6,leukemiainhibitoryfactor(LIF),ciliary LIF,CNTF,OSM,IL-11,andCT-1.Thesecytokines
neurotropic factor (CNTF), oncostatin M (OSM), are characterized by a four (cid:11) helix bundle structure
IL-11, cardiotropin 1 (CT-1), and possibly the novel (Bazan, 1990) and they play pivotal roles in the
neurotrophin 1/B cell-stimulating factor 3 (NNT-1/ immune,hematopoietic,nervous,cardiovascular,and
BSF-3). They play pivotal roles in the immune, endocrine systems, as well as in bone metabolism,
hematopoietic, nervous, cardiovascular, and endo- inflammation, and acute-phase response by regulat-
crine systems, as well as in bone metabolism, inflam- ing cell growth, differentiation, cell survival, and
mation, and acute-phase response. Gp130, originally expression of a variety of functions (Hirano et al.,
identified as a signal-transducing subunit for IL-6 1997; Hirano, 1998; Heinrich et al., 1998). Much
receptor (IL-6R), is shared among the receptors for evidence has been accumulated, leading to the estab-
the IL-6 cytokine family. Janus kinases (JAKs) and lishment of a variety of concepts about cytokines in
signal transducer and activator of transcription general: the establishment of pleiotropy and redun-
(STATs) play essential roles in signal transduction dancyaspropertiesofcytokinefunction,thecytokine
through cytokine rceptors. Other pathways involving receptor superfamily, the sharing of a signal-transdu-
src family tyrosine kinases, RAS, mitogen-activated cing receptor subunit among several cytokine recep-
protein kinases (MAPK), and phosphatidylinositol tors, and the agonistic activity of the complex of
3-kinase(PI-3kinase),andtheinterplayamongthem, cytokine and its receptors in certain cytokines. The
are critically involved in the biological activities of molecular mechanism of functional redundancy is
cytokines. explained at least in part by the sharing of gp130, a
Cytokines can simultaneously generate contra- signal-transducing receptor subunit, among the
dictory signals in the same target cells and the receptors for the IL-6 cytokine family and low-
balance of each contradictory signal may determine affinity LIFR subunit (LIFR(cid:12), also called (cid:11)) among
the final output of the cytokine signals to express LIFR, CNTFR, and human OSMR (Hirano et al.,
unified biological activity (signal orchestration). The 1997; Hirano, 1998; Heinrich et al., 1998) (Figure 1).
complex of cytokine and its soluble form of receptor Studies on the signal transduction mechanisms of
acts like a cytokine with novel target specificity interferonsanderythropoietinhaveledtoinsightinto
(receptor conversion). These mechanisms may be the molecular mechanisms of signal transduction
involved in the generation of functional pleiotrophy through cytokine receptors. It is now known that
of cytokine. JAKsandSTATs(seechapteronIL-6Receptor)play
524 Toshio Hirano and Toshiyuki Fukada
Figure1 Sharingofreceptorsubunitsincytokinereceptors.Gp130issharedbythereceptorsforIL-6,IL-11,LIF,
CNTF, OSM, and CT-1. m, mouse; h, human.
IL-6 IL-11 mOSM hOSM LIF CNTF CT-1
Conserved
cytokines
WSXWS
motif
CNTFRa CT-1Ra ?
IL-6Ra IL-11Ra
Box1
Box2
OSMRb LIFRb LIFRb LIFRb
gp130 gp130 gp130 gp130 gp130 gp130
essential roles in cytokine function (Darnell et al., OSM, and CT-1 induce macrophage differentiation
1994; Ihle et al., 1994; Schindler and Darnell, 1995; in a myeloid leukemic cell line, M1 (Abe et al., 1991;
Ihle,1996;Darnell,1997;HorvathandDarnell,1997). HiltonandGough,1991;Begley,1994;Pennicaetal.,
Furthermore, other pathways involving src family 1995). IL-6, IL-11, LIF, and OSM all induce growth
tyrosine kinases, Ras, MAP kinase, PI-3 kinase, and ofmyelomacells.IL-6,LIF,andIL-11enhanceIL-3-
as yet unidentified components participate, and the dependentcolonyformationofprimitiveblastcolony-
interplay among them is critically involved in the forming cells (Ikebuchi et al., 1987; Musashi et al.,
biologicalactivitiesofcytokines.Moreover,cytokines 1991). IL-6, LIF, IL-11, and OSM stimulate the
can simultaneously generate contradictory signals biosynthesis of acute-phase proteins in hepatocytes
in the same target cells and the balance of each (Leng and Elias, 1997). The functional redundancy
contradictory signal may determine the final output observed among these IL-6-related cytokine subfam-
of the cytokine signals to express unified biological ily is mostly explained by the sharing of receptor
activity. Such a mechanism, called signal orchestra- subunit gp130 among the IL-6 cytokine family and
tion,maybeinvolvedatleastinpartintheexpression LIFR(cid:12) among LIFR, CNTFR, and human OSMR.
of functional pleiotropy of cytokines. The sharing of a receptor subunit among different
cytokinereceptorsisnotauniquefeaturefortheIL-6
cytokinefamilyreceptors,butratherageneralfeature
of the cytokine receptor system. GM-CSF, IL-3, and
FUNCTIONAL REDUNDANCY IL-5 receptors share a common (cid:12) subunit (Miyajima
etal.,1992).The(cid:12)chainoftheIL-2RissharedbyIL-
AMONG THE IL-6 FAMILY
15R,andthecommon(cid:13) chainofIL-2R((cid:13)c)isshared
CYTOKINES
by IL-4R, IL-7R, IL-9R, and IL-15R (Sugamura
et al., 1995; Taniguchi, 1995). Thus, the molecular
IL-6, LIF, CNTF, OSM, IL-11, and CT-1 constitute mechanisms of redundancy in cytokine activity could
the IL-6-related cytokine subfamily because of their beexplainedatleastinpartbythesharingofreceptor
functional redundancy, structural similarity, and subunits among several cytokine receptors. Since
sharingofthereceptorsubunit(Table1andTable2). OSM functions through the OSM-specific and LIF/
They regulate cell growth, cell survival, and cell OSM shared receptors in humans, while it functions
differentiationinawidevarietyofbiologicalsystems, through the OSM-specific receptor in mice, the
including immune response, hematopoiesis, inflam- reports on biological roles of OSM in mice using
mation,neurogenesis,andosteogenesis.Furthermore, human OSM should be interpreted with care (see the
they often show functional redundancy; IL-6, LIF, chapters on OSM and OSMR).
IL-6 Ligand and Receptor Family 525
Table 1 Biochemical and physiological properties of human IL-6-type cytokines
Potential No. No. Tissues of Stimulus Functions
glycosylation cysteine S–S expression molecules
sites residues bonds
IL-6 2 4 2 Many tissues, IL-1, TNF(cid:11), Hematopoiesis
(184aa) including blood, TGF(cid:12), OSM,
Differentiation and
cartilage, bone IL-4, IL-11
proliferation of
marrow, skin,
B and T cells
lung, and CNS
Stimulation of proliferation
of mesangial cells and
keratinocytes
Regulation of acute phase
protein (APP) synthesis
Upregulation of TIMP-1
Stimulation of ACTH
production
Osteoclast development
IL-11 0 0 0 Hematopoietic tissues, IL-1, TGF(cid:12) Hematopoiesis
(178aa) lung, gastrointestinal
Growth control of
tract, bone, CNS,
epithelial cells
thymus, connective
tissues, skin, Osteoclast development
uterus and testis
Neurogenesis
Stimulator of APP
synthesis
Upregulation of TIMP-1
Inhibition of adipogenesis
LIF 6 6 3 Many tissues, IL-1, TNF(cid:11), Hematopoiesis
(180aa) including heart, liver, TGF(cid:12), IL-8,
Differentiation factor for
endometrium, EGF, IL-3, OSM,
pituitary corticotropic cells
pituitary, CNS, gut, LPS, PDGF,
kidney, lung, IL-4, IL-11 Regulation of APP
and thymus synthesis
Upregulation of TIMP-1
Inhibition of differentiation
of ES cells
Switch to cholinergic
function of sympathetic
neurons
Proliferation of myoblasts
CNTF 0 1 0 Nervous system Increased synthesis Anti-apoptotic effect
(200aa) in astrocytes after after nerve injury
injury. Released
Inhibition of developmentally
after injury of
determined apoptosis
peripheral nerve
cells Promotes the cholinergic
phenotype in sympathetic
nerves
Activation of choline
acetyltransferase
in motor neurons
Activation of outgrowth
of neurites in vivo
526 Toshio Hirano and Toshiyuki Fukada
Table 1 (Continued)
Potential No. No. Tissues of Stimulus Functions
glycosylation cysteine S–S expression molecules
sites residues bonds
Downregulation of
proinflammatory cytokines
(IL-1, IL-18) and PGE
2
Regulation of APP synthesis
Upregulation of CNTFR
and NGFR
CT-1 0 2 ? Heart, skeletal muscle, ? Induction of hypertrophy
(201aa) ovary, colon, prostate, of neonatal cardiac
testis, fetal kidney, monocytes
and lung
Inhibition of cardiac
myocyte apoptosis
Survival factor for spinal
motor neurons
Stimulation of cholinergic
differentiation of
sympathetic neurons
Red blood cell counts
Inhibition of LPS-
stimulated TNF(cid:11)
production
Stimulation of APP synthesis
OSM 2 5 2 Testis, blood T cell activators, Survival of Sertoli cells
(196aa) PMA, IL-2, and gonocytes
IL-3, EPO
Upregulation of LDLR
Regulation of APP synthesis
Induction of cytokines
(IL-6, G-CSF, GM-CSF,
LIF, bEGF)
Effect on extracellular matrix
Upregulation of adhesion
molecules in endothelial cells
RECEPTOR CONVERSION solubleformofitsreceptor,respectively(Gearingand
Cosman, 1991), suggesting that IL-12 acts on target
A novel mechanism generating cells in a manner similar to the complex of IL-6
and soluble IL-6R. Another example is a CNTFR(cid:11)
functional diversity of cytokine
that is anchored to the cell membrane by a
glycosylphosphatidylinositol(GPI)linkage.Thecom-
A complex ofIL-6 and asoluble form ofIL-6R(cid:11)can plex of soluble CNTFR(cid:11) and CNTF acts on cells
activate signal transduction in cells expressing only expressingLIFR(cid:12) andgp130(Davisetal.,1993).The
the gp130 receptor subunit. This type ofarrangement complex of IL-11 and the soluble form of IL-11R
isnotuniquetotheIL-6Rsystem.IL-12consistsofa also functions through gp130 (Baumann et al., 1996;
disulfide heterodimer of 40kDa (p40) and 35kDa Neddermann et al., 1996).
(p35) subunits (Kobayashi et al., 1989). The peptide Basedonthesefacts,weoriginallyproposedanovel
sequences of p35 and p40 resemble IL-6 and the mechanism by which the cytokine system generates
IL-6 Ligand and Receptor Family 527
Table 2 Biochemical and physiological properties of IL-6-type receptors
Extracellular Transmembrane Intracellular Potential Phenotypes of
domain (aa) domain (aa) domain (aa) glycosylation knockout mice
sites
IL-6(cid:11) (449aa) 339 28 82 5 Not examined
IL-11R(cid:11) (400aa) 343 26 31 2 Female infertility
Normal hematopoisis
CNTFR(cid:11) (352aa) 352 4 Mice die between 12 and
24 hours after birth
Defect in motor neuron
development
LIFR(cid:12) (1053aa) 789 26 238 19 Perinatal lethality
Defects in placental
architecture
Decrease in bone volume
Reduction of astrocyte
number in spinal cord
and brainstem
Loss in motor neurons of
the facial nucleus and
lumber spinal cord
Reduction in neurons of
the nucleus ambiguous
Elevated stores of glycogen
in late gestation fetal liver
OSMR(cid:12) (952aa) 712 22 218 15 Not examined
gp130 (896aa) 597 22 277 10 Embryonic lethality
between day 12.5 and
term
Heart abnormality
Hematopoietic abnormality
functional diversity (Figure 2) (Hirano, 1994; Hirano receptor conversion may be applied to a wide range
et al., 1994). We wish to call this mechanism receptor of receptor systems, for example, the receptors for
conversion. A complex consisting of a soluble cyto- glial cellline-derivedneurotropicfactor(GDNF)and
kine receptor and its corresponding cytokine ligand neurturin (NTN). Both the GDNF and NTN recep-
acquires a different target specificity from the ori- tors consist of a ligand-specific GPI-anchored (cid:11)
ginal cytokine, leading to the expression of distinct chain and a common signal-transducing receptor
functions from those of the original cytokine. subunit, Ret, which is a receptor tyrosine kinase
Actually, double transgenic mice expressing human (Jingetal.,1996;Treanoretal.,1996;Buj-Belloetal.,
IL-6 and IL-6R(cid:11) showed myocardial hypertrophy 1997; Klein et al., 1997). Receptor conversion con-
(Hirota et al., 1995), extraordinary expansion of tributestogeneratingthefunctionaldiversityofcyto-
hematopoietic progenitor cells (Peters et al., 1997), kines and may also play pathological roles in various
and nodular regenerative hyperplasia and adenomas diseases, since an increase in the serum-soluble form
of the liver (Maione et al., 1998), indicating that the of various cytokine receptors has been reported to
complex of IL-6 and the soluble form of IL-6R(cid:11) acts occur in a variety of diseases. Furthermore, novel
on heart muscle cells and hematopoietic stem cells drugs could be designed based on this model. A
that express gp130, on which IL-6 alone cannot act. bioactive designer cytokine is being developed, which
Thus,byformingacomplex,IL-6apparentlyacquires is composed of soluble IL-6R(cid:11) and IL-6 linked by a
novel biological activities. Thus, the mechanism of flexible peptide chain (Fischer et al., 1997).
528 Toshio Hirano and Toshiyuki Fukada
Figure 2 Receptor conversion, a novel mechanism Zhong et al., 1994; Lai et al., 1995; Nakajima et al.,
generatingcytokinediversity.Acytokineactsonthe 1995). In response to cytokine stimulation, phos-
cells (target cell 1) that express a specific receptor. phorylated STATs are dimerized and translocated
With certain cytokines, such as IL-6 and CNTF, a
into the nucleus, leading to the expression of genes
complex composed of the cytokine and a soluble
with STAT recognition sites. Phosphorylated STAT1
form of its receptor subunit can activate the signal
was shown to be associated with (cid:12) subunit (a 97kDa
transduction pathway in cells (target cell 2) that
component)ofthenuclearpore-targetingcomplexvia
express only a receptor subunit and do not respond
theNPI-1familyof(cid:11)subunit(a58kDacomponent).
to the cytokine alone.
STAT1-binding domain of NPI-1 is located in the
Cytokine Complex of cytokine C-terminalregion,whichisdistinctfromtheSV40large
and soluble receptor
T antigen nuclear localization signal-binding region
(Sekimoto et al., 1997; Sekimoto and Yoneda, 1998).
Furthermore, a nuclear small GTP-binding protein
Ran, which is an essential factor for active nuclear
protein transport, is involved in, and its GTP hydrol-
ysis activity is required for, the IFN(cid:13)-dependent
nuclear transport of STAT1 (Sekimoto et al., 1996).
In addition to the JAK/STAT pathway, multiple
signaling molecules are tyrosine-phosphorylated in
response to the IL-6 family of cytokines (Figure 3).
Target 1 Target 2
CNTF, LIF, OSM, and IL-6 induce tyrosine phos-
phorylationofphospholipaseC(cid:13),SHP-2(aphospho-
tyrosine phosphatase, also called PTP1-D, SHPTP-2,
PTP2C,andSyp),whichisamammalianhomologof
ACTIVATION OF MULTIPLE Drosophila corkscrew (CWS), pp120, Shc, Grb2,
Raf-1, and ERK1 and ERK2 (Boulton et al., 1994).
SIGNAL TRANSDUCTION
IL-11 induces tyrosine phosphorylation of SHP-2 in
PATHWAYS BY THE IL-6 FAMILY
mouse3T3-L1cells.Furthermore,SHP-2isinducibly
CYTOKINES associatedwithgp130(Fuhreretal.,1995;Stahletal.,
1995; Fukada et al., 1996) and JAK2 (Fuhrer et al.,
Involvement in regulation of cell 1995). The Ras/MAPK pathway is activated by
the IL-6 cytokine family (Nakafuku et al., 1992;
growth, differentiation and survival
Daeipour et al., 1993; Boulton et al., 1994; Kumar
et al., 1994; Fukada et al., 1996; Berger and Hawley,
JAK family tyrosine kinases (JAK1, JAK2, JAK3, 1997). The activation of the Ras/MAPK pathway is
TYK2) are involved in the signal transduction of possibly mediated by SHP-2 (Fukada et al., 1996;
cytokinesandhormones(Ihleetal.,1994;Ihle,1996). Berger and Hawley, 1997) and/or Shc (Ernst et al.,
Cytokines induce receptor aggregation, resulting in 1994; Kumar et al., 1994), which bind a Grb2/SOS
the activation of JAK family tyrosine kinases. These complex. Gp130 stimulation induces tyrosine phos-
events eventually induce the tyrosine phosphoryla- phorylation of both Gab1 and Gab2, which have
tion of STAT, which was originally identified as an structuralsimilaritiestoDrosophilaDOS,ordaughter
interferon-activated transcription factor by Darnell of sevenless (Takahashi-Tezuka et al., 1998; Nishida
andhiscolleagues(Darnelletal.,1994;Schindlerand et al., 1999), being complexed with SHP-2 and PI-3
Darnell, 1995). kinase and involved in MAP kinase activation. Gab1
JAK1, JAK2, and TYK2 associate constitutively andGab2arealsotyrosinephosphorylatedinresponse
with gp130 and are tyrosine-phosphorylated in re- to EGF, insulin, and c-Met stimulation, T and B cell
sponse to IL-6, CNTF, LIF, OSM, or IL-11 (Berger antigenreceptors(Guetal.,1998;Nishidaetal.,1999).
et al., 1994; Lutticken et al., 1994; Matsuda et al., Both Gab1 and Gab2 have binding sites for PLC(cid:13),
1994; Stahl et al., 1994). JAK1 is considered to be PI-3 kinase, SHP-2, and Grb2 (Holgado-Madruga
a major kinase among this family, activating STAT3 etal.,1996;Weidneretal.,1996)andshowstructural
through gp130 (Guschin et al., 1995). Cells from similarities with IRS-1, IRS-2, and Drosophila DOS.
JAK1 knockout mice could not respond to the IL-6 These DOS-related family molecules may act as
familycytokines(Rodigetal.,1998).TheIL-6family universal docking molecules linking a variety of
cytokines activate STAT3, STAT1, and STAT5 receptors to downstream signaling molecules. In fact,
(Akira et al., 1994; Fujitani et al., 1994, 1997; IRS-1 is tyrosine phosphorylatedin response to IL-2,
IL-6 Ligand and Receptor Family 529
Figure 3 Distinct cytoplasmic regions of gp130 are involved in different
signal transduction pathways.
gp130
JAK JAK
Gab1/2
PI-3K SHP-2 Y759
Grb2
Sos Y767
774 (133)
STAT3 Y814 STAT3
Ras Y905
? Y915 c-myc
918 (277) Cyclin A p21
Raf Bcl-2
c-myb Cyclin D p27
Erk1/2 c-myc CDC25A
Neurite outgrowth Anti- G1 S G2/M
in PC12 cell STAT3 apoptosis Cell cycle transition
p19 ink4D Cell proliferation in BAFB03 cell
Growth arrest and differentiation
in M1 cell
IL-4, IL-7, IL-9, IL-15, OSM, and interferons, in cytokine are different, and since each cytokine
additiontoinsulin(Keeganetal.,1994;Johnstonetal., receptor has different binding affinities for a variety
1995;Yinetal.,1995;Burfootetal.,1997).IRS-2acts of signaling molecules, each cytokine is capable of
asanadaptermoleculelinkinggrowthhormonerecep- expressingauniquebiologicalactivity.Anotherques-
tor to PI-3 kinase. Src family tyrosine kinases, such tion is how a single cytokine can exert distinct bio-
as Btk, Tec, Fes, and Hck (Ernst et al., 1994, 1996; logical activities on different target cells. There are
Matsuda et al., 1995a,b) are activated by the IL-6 severalpointstobeconsidered.First,differentsetsof
cytokinefamily,aswellasbyavarietyofothercytokines signaltransductionpathways(despitetheexistenceof
(Taniguchi,1995).Amongthem,TecandBtkassociate partial redundancy among them) could simply be
with,andarepossiblyactivatedbyJAKs,andTecmay activated in different targets through a given cyto-
be one of the adapter molecules linking the cytokine kine, due to differences in the expression pattern of
receptortoPI-3kinase(Takahashi-Tezukaetal.,1997). each signaling molecule (Figure 4a). Second, even if a
These multiple signal transduction pathways are cytokine receptor can induce the same set of signal
variably involved in the regulation of cell growth, transductionpathwaysindifferenttargets,eachtarget
survival, and differentiation by interacting with each cell could respond to the cytokine stimulation differ-
other, as described in Figure 3 and in the chapter on entlybecausetheexpressionand/oractivationstateof
the IL-6 receptor. other molecules affecting each signal transduction
pathway negatively or synergistically is different or
because the final transcriptional activation of target
SIMULTANEOUS GENERATION
genes of the signal transduction pathway is different
OF CONTRADICTORY SIGNALS among different targets (Figure 4b). Third, the bal-
THROUGH A CYTOKINE anceorinterplay(inhibitoryorsynergisticinteraction)
among the signaling pathways could determine the
RECEPTOR
eventual outcome of the signal transduction through
the receptor in a given target cell (Figure 4c).
Orchestrating model
Relevant findings obtained through studies on
gp130-mediated signals are:
Cytokines exert a variety of biological activities
through specific receptors. Since the expression 1. gp130 stimulation can simultaneously induce
pattern of each cytokine receptor and that of a opposite signals, e.g. growth-enhancing and
530 Toshio Hirano and Toshiyuki Fukada
growth-suppressingsignalsareinducedinM1cells Figure 4 Models for signal transduction pathways in-
(Nakajima et al., 1996) volved in the expression of a target-specific biological
2. gp130 can deliver at the same time both positive activities by a single cytokine. (a) Different signal path-
andnegativesignalsaffectingneuriteoutgrowthin ways are generated in different target cells through the
samecytokinereceptor.(b)Thesamesetofsignaltrans-
PC12 cells (Ihara et al., 1997)
duction pathways is generated, but other molecules
3. CNTF promotes differentiation of cortical pre-
affectingthesignaltransductionpathwaysaredifferently
curser cells into astrocytes through activation of
expressed in each target cell. (c) Orchestrating model:
STAT3, while simultaneous activation of MAPK
contradictorysignalpathwaysaresimultaneously gener-
is rather suppressive for CNTF activation (Bonni ated in a single target cell and the balance or interplay
et al., 1997) among them eventually determines the outcome. Such a
3. gp130 can drive G to S phase cell cycle transition situation could be orchestrated by a conductor to effect
1
signal and, at the same time, induce p21 cyclin- a directed biological action. The variable combination
dependent kinase inhibitor from the distinct cyto- of mechanisms determines the final outcome of the
plasmic regions in the same target cells (Fukada signaling.
et al., 1998).
These findings are quite surprising, since one might (a)
reasonably expect that a cytokine would only induce
twwciaohelnlilca-hcicsotiorevelriiptdcyoiitnrsiatnetsdeaidmignusiivltgteuannmnaeltosoarurtognseleyetcxrcbpoeorslelit.sshsAfaaacpstuioomnpriitflsoaitetridmicoubbslisaoigetlrnoiovaganlis--, AB ssiiggnnaall CD ssiiggnnaall FE ssiiggnnaall GH ssiiggnnaall
through the caspase cascade and anti-apoptotic sig-
(b)
nals through NF(cid:20)B activation (Liu et al., 1996).
TipFbnoehuttruraeatcsnhc,tteeiivclralamyulttleooadsrkriemib,nsyuebiglgotanrtanoahndlweipnot2ghgu1rsfolapaywcnatttdohhtrowGsfaa(1cSiyntcscod,hyrucraelcriinenebcdseercapoterthnetoetrasrslha.b,odha1wiacl9avnt9one9trc)oaye. a AB ssiiggnnaall CD ssiiggnnaall BA ssiiggnnaall DC ssiiggnnaall b
and/orinterplayofeachpathwaycoulddeterminethe
final outcome of the stimulation. Such a situation (c)
could be orchestrated by a conductor to exert an
unified output. We wish to call this model signal
orchestration (Figure 4c). It is likely that the variable
combinationsofthesemechanismsareinvolvedinthe
determination of the final outcome of the cytokine
signaling.
A D
B C
C D A B
POSITIVE AND NEGATIVE
FEEDBACK MECHANISMS
Conductor Conductor
The balance of each signal transduction pathway
could be influenced by a variety of factors that
determine the duration and intensity of each signal- negative regulator of STAT3, such as a postulated
ing.Inthissense,positiveornegativefeedbackmech- STAT phosphotyrosine phosphatase (Haspel et al.,
anisms may be crucial to determine the balance. The 1996), or the upregulation of STAT3. In fact, the
activationstateofSTAT3inIL-6-stimulatedM1cells STAT3 gene is autoregulated by STAT3 in M1 cells
persists for as long as 24 hours after stimulation (Ichiba et al., 1998) and this may partly contribute
(Nakajima et al., 1996; Yamanaka et al., 1996). Such to the sustained activation of STAT3 in M1 cells.
prolonged activation of a particular signal transduc- Concerning a negative regulator for STAT, the nat-
tion pathway should affect the outcome of the signal ural existence of potentially dominantly suppressive
transduction. The sustained activation of STAT3 in variants of STAT3 and STAT5 has been reported
M1 cells may be induced by either the absence of a (Caldenhoven et al., 1996; Wang et al., 1996).
IL-6 Ligand and Receptor Family 531
MAP kinase is also implicated as a negative regu- interplay between a given cytokine and others would
latorforSTAT3activation(Jainetal.,1998;Sengupta modify the final output of a cytokine action. IL-6
et al., 1998). Phosphotyrosine phosphatases are cri- stimulation induces association between gp130 and
tical negative or positive regulators for cytokine and receptor tyrosine kinase erbB2, following tyrosine
growth factor-mediated signal transduction pathway. phosphorylation and kinase activation of erbB2 in
SHP-1,anSH2domaincontainingaphosphotyrosine prostate carcinoma cells. This activation of erbB2
phosphatase,is thoughttoactasanegativeregulator contributes to the IL-6-induced activation of MAPK
for erythropoietin receptor-mediated signal transduc- ERK2 in prostate carcinoma cells (Qiu et al., 1998).
tion by inactivating JAK2 (Klingmuller et al., 1995). Gp130 can induce neurite outgrowth in PC12 cells
SHP-2 is also suggested negatively to regulate the whenpretreatedwithNGF.NGFstimulationinhibits
expression of acute-phase genes (Kim et al., 1998), IL-6-induced activation of STAT3, which is inhibi-
although SHP-2 is considered to act as a positive tory for neurite outgrowth, providing an example of
regulator in MAPK activation (Tonks and Neel, the modification of cytokine signaling by growth
1996; Neel and Tonks, 1996). factor signaling (Ihara et al., 1997).
In addition to these, the family molecules that can Such a crosstalk is observed in other cytokines.
bind to SHP-2, SHP-1, and Grb2 have been cloned: Growth hormone stimulation induces tyrosine phos-
these are the signal-regulatory protein (SIRP) family phorylation of the intracellular domain of EGF
(Kharitonenkov et al., 1997) and SHP substrate 1 receptor (EGFR), indicating that growth hormone
(SHPS-1)(Fujiokaetal.,1996),whichisamemberof utilizes EGFR to activate the Ras/MAPK pathway
theSIRP(cid:11)family.SIRP(cid:11)1isasubstrateforactivated (Yamauchi et al., 1997). IFN(cid:13) and TGF(cid:12) have op-
receptor tyrosine kinases and its tyrosine-phospho- positeeffectsondiversecellularfunctions,eveninthe
rylated form binds SHP-2 through SH2 interactions same target cells. IFN(cid:13) inhibits TGF(cid:12)-induced sig-
and acts as its substrate. It has negative regulatory naling events, such as SMAD3 phosphorylation and
effects on insulin, epidermal growth factor (EGF), activation of TGF(cid:12)-responsive genes. IFN(cid:13) induces
and platelet derived growth factor (PDGF)-induced an antagonistic SMAD (SMAD7) through activation
growth, most likely through the inhibition of MAPK of JAK1 and STAT1, indicating a mechanism of
activity (Kharitonenkov et al., 1997). Furthermore, transmodulation of TGF(cid:12) signaling by IFN(cid:13) (Ulloa
STAT3 induces a SH2 domain-containing molecule etal.,1999).Itispossiblethatsuchacrosstalkamong
designated as SOCS-1/JAB/SSI-1 (Endo et al., 1997; cytokine receptors is one of the important factors
Naka et al., 1997; Starr et al., 1997), which is struc- determiningthecell’sfate,andinlinewiththenotion
turally related to CIS, a cytokine-inducible SH2 pro- that different sets of signal transduction could be
tein(Yoshimuraet al.,1995).SOCS-1/JAB/SSI-1can generated in different targets, through a given cyto-
bind JAK and inhibit its kinase activity and thereby kine receptor (Figure 4a). Further identification of
suppress the tyrosine phosphorylation of gp130 and crosstalk pathways among cytokines and/or growth
subsequent activation of STAT. factors would contribute to a molecular explanation
A family of protein inhibitor of activated STAT ofthefeaturesofcytokinefunctions:functionalpleio-
(PIAS) proteins are identified as another group of tropy, and redundancy.
STAT inhibitors which bind to STATs and inhibit
DNA-binding activity of STATs in a stimulation-
References
dependent manner. For instance, PIAS1 blocks the
DNA-binding activity of STAT1, but not other
Abe, T., Ohno, M., Sato, T., Murakami, M., Kajiki, M., and
STATs,andinhibitsSTAT1-mediatedgeneactivation
Kodaira, R. (1991). ‘‘Differentiation induction’’ culture of
in response to interferon. The in vivo PIAS1-STAT1
human leukemic myeloid cells stimulates high production of
interaction requires phosphorylation of STAT1 on macrophage differentiation inducing factor. Cytotechnology 5,
Tyr701 (Liu et al., 1997). PIAS3 is another member S75–S93.
whichspecificallyassociateswithandinhibitsSTAT3 Akira, S., Nishio, Y., Inoue, M., Wang, X. J., Wei, S.,
Matsusaka, T., Yoshida, K., Sudo, T., Naruto, M., and
(Chung et al., 1997).
Kishimoto, T. (1994). Molecular cloning of APRF, a novel
IFN-stimulated gene factor 3 p91-related transcription factor
involved in the gp130-mediated signaling pathway. Cell 77,
63–71.
CROSSTALK BETWEEN GP130
Argetsinger,L.S.,Norstedt,G.,Billestrup,N.,White,M.F.,and
SIGNALING AND OTHERS Carter-Su,C.(1996).Growthhormone,interferon-gamma,and
leukemia inhibitory factor utilize insulin receptor substrate-2
inintracellularsignaling.J.Biol.Chem.271,29415–29421.
Signalings through a cytokine receptor crosstalk with Baumann, H., Wang, Y., Morella, K. K., Lai, C. F., Dams, H.,
those through other receptors. Such a crosstalk or Hilton, D. J., Hawley, R. G., and Mackiewicz, A. (1996).
532 Toshio Hirano and Toshiyuki Fukada
ComplexofthesolubleIL-11receptorandIL-11actsasIL-6- Ernst, M., Gearing, D. P., and Dunn, A. R. (1994). Functional
typecytokineinhepaticandnonhepaticcells.J.Immunol.157, andbiochemicalassociationofHckwiththeLIF/IL-6receptor
284–290. signal transducing subunit gp130 in embryonic stem cells.
Bazan,J.F.(1990).Haemopoieticreceptorsandhelicalcytokines. EMBOJ.13,1574–1584.
Immunol.Today11,350–354. Ernst, M., Oates, A., and Dunn, A. R. (1996). Gp130-mediated
Begley,C.G.(1994).TheSCLtranscriptionfactoranddifferential signal transduction in embryonic stemcells involves activation
regulation of macrophage differentiation by LIF, OSM and of Jak and Ras/mitogen-activated protein kinase pathways.
IL-6.StemCells(Dayt).12,143–151. J.Biol.Chem.271,30136–30143.
Berger, L. C., and Hawley, R. G. (1997). Interferon-beta inter- Fischer, M., Goldschmitt, J., Peschel, C., Brakenhoff, J. P.,
rupts interleukin-6-dependent signaling events in myeloma Kallen, K. J., Wollmer, A., Grotzinger, J., and Rose-John, S.
cells.Blood89,261–271. (1997). I. A bioactive designer cytokine for human hemato-
Berger, L. C., Hawley, T. S., Lust, J. A., Goldman, S. J., and poietic progenitor cell expansion. Nat. Biotechnol. 15, 142–
Hawley, R. G. (1994). Tyrosine phosphorylation of JAK- 145.
TYK kinases in malignant plasma cell lines growth-stimulated Fuhrer,D.K.,Feng,G.S.,andYang,Y.C.(1995).Sypassociates
byinterleukins6and11.Biochem.Biophys.Res.Commun.202, with gp130 and Janus kinase 2 in response to interleukin-11
596–605. in 3T3-L1 mouse preadipocytes. J. Biol. Chem. 270, 24826–
Bonni, A., Sun, Y., Nadal-Vicens, M., Bhatt, A., Frank, D. A., 24830.
Rozovsky, I., Stahl, N., Yancopoulos, G. D., and Fujioka,Y.,Matozaki,T.,Noguchi,T.,Iwamatsu,A.,Yamao,T.,
Greenberg, M. E. (1997). Regulation of gliogenesis in the Takahashi,N.,Tsuda,M.,Takada,T.,andKasuga,M.(1996).
central nervous system by the JAK-STAT signaling pathway. Anovelmembraneglycoprotein, SHPS-1,thatbindstheSH2-
Science278,477–483. domain-containing protein tyrosine phosphatase SHP-2 in
Boulton,T.G.,Stahl,N.,andYancopoulos,G.D.(1994).Ciliary response to mitogens and cell adhesion. Mol. Cell Biol. 16,
neurotrophic factor/leukemia inhibitory factor/interleukin 6887–6899.
6/oncostatinMfamilyofcytokinesinducestyrosinephosphor- Fujitani, Y., Hibi, M., Fukada, T., Takahashi-Tezuka, M.,
ylationofacommonsetofproteinsoverlappingthoseinduced Yoshida, H., Yamaguchi, T., Sugiyama, K., Yamanaka, Y.,
by other cytokines and growth factors. J. Biol. Chem. 269, Nakajima, K., and Hirano, T. (1997). An alternative pathway
11648–11655. for STAT activation that is mediated by the direct interaction
Buj-Bello, A., Adu, J., Pinon, L. G., Horton, A., Thompson, J., betweenJAKandSTAT.Oncogene14,751–761.
Rosenthal, A., Chinchetru, M., Buchman, V. L., and Fujitani, Y., Nakajima, K., Kojima, H., Nakae, K., Takeda, T.,
Davies, A. M. (1997). Neurturin responsiveness requires a and Hirano, T. (1994). Transcriptional activation of the IL-6
GPI-linked receptor and the Ret receptor tyrosine kinase. responseelementinthejunBpromoterismediatedbymultiple
Nature387,721–724. Stat family proteins. Biochem. Biophys. Res. Commun. 202,
Burfoot,M.S.,Rogers,N.C.,Watling,D.,Smith,J.M.,Pons,S., 1181–1187.
Paonessaw, G., Pellegrini, S., White, M. F., and Kerr, I. M. Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M.,
(1997). Janus kinase-dependent activation of insulin receptor Fujitani, Y., Yamaguchi, T., Nakajima, K., and Hirano, T.
substrate1inresponsetointerleukin-4,oncostatinM,andthe (1996). Two signals are necessary for cell proliferation
interferons.J.Biol.Chem.272,24183–24190. induced by a cytokine receptor gp130:involvement of STAT3
Caldenhoven, E., van Dijk, T. B., Solari, R., Armstrong, J., in anti-apoptosis. (manuscript submitted.) Immunity 5, 449–
Raaijmakers, J. A. M., Lammers, J. W. J., Koenderman, L., 460.
and de Groot, R. P. (1996). STAT3beta, a splice variant of Fukada,T.,Ohtani,T.,Yoshida,Y.,Shirogane,T.,Nishida,K.,
transcription factor STAT3, is a dominant negative regulator Nakajima,K.,Hibi,M.,andHirano,T.(1998).STAT3orches-
oftranscription.J.Biol.Chem.271,13221–13227. trates contradictory signals in cytokine-induced G1 to S cell-
Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., and cycletransition.EMBOJ.17,6670–6677.
Shuai,K.(1997).SpecificinhibitionofStat3signaltransduction Gearing, D. P., and Cosman, D. (1991). Homology of the p40
byPIAS3.Science278,1803–1805. subunit of natural killer cell stimulatory factor (NKSF) with
Daeipour,M.,Kumar,G.,Amaral,M.C.,andNel,A.E.(1993). the extracellular domain of the interleukin-6 receptor [letter].
Recombinant IL-6 activates p42 and p44 mitogen-activated Cell66,9–10.
protein kinases in the IL-6 responsive B cell line, AF-10. Gu, H., Pratt, J. C., Burakoff, S. J., and Neel, B. G. (1998).
J.Immunol.150,4743–4753. Cloningofp97/Gab2,themajorSHP2-bindingproteininhema-
Darnell,J.E.Jr.(1997).STATsandgeneregulation.Science277, topoietic cells, reveals a novel pathway for cytokine-induced
1630–1635. geneactivation.Mol.Cell.2,729–740.
Darnell,J.E.Jr.,Kerr,I.M.,andStark,G.R.(1994).Jak-STAT Guschin, D., Rogers, N., Briscoe, J., Witthuhn, B., Watling, D.,
pathwaysandtranscriptionalactivationinresponsetoIFNsand Horn, F., Pellegrini, S., Yasukawa, K., Heinrich, P.,
otherextracellularsignalingproteins.Science264,1415–1421. Stark,G.R.,Ihle,J.N.,andKerr,I.M.(1995).Amajorrole
Davis, S., Aldrich, T. H., Ip, N. Y., Stahl, N., Scherer, S., for the protein tyrosine kinase JAK1 in the JAK/STAT signal
Farruggella, T., DiStefano, P. S., Curtis, R., Panayotatos, N., transduction pathway in response to interleukin-6. EMBO J.
Gascan, H., Chevalier, S., and Yancopoulos, G. D. (1993). 14,1421–1429.
Released form of CNTF receptor a components as a soluble Haspel,R.L.,Salditt-Georgieff,M.,andDarnell,J.E.Jr.(1996).
mediatorofCNTFresponses.Science259,1736–1739. The rapid inactivation of nuclear tyrosine phosphorylated
Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Stat1depends upon a protein tyrosine phosphatase.EMBO J.
Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., 15,6262–6268.
Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F.,
Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., and and Graeve, L. (1998). Interleukin-6-type cytokine signalling
Yoshimura, A. (1997). A new protein containing an SH2 through the gp130/Jak/STAT pathway. Biochem. J. 334,
domainthatinhibitsJAKkinases.Nature387,921–924. 297–314.