IL-4 Receptor

10 Pages·0.119 MB·English

by  Keegan A.D.

IL-4 Receptor
Achsah D. Keegan
*
Immunology Department, Holland Laboratory of the American Red Cross, 15601 Crabbs Branch Way,
Rockville, MD 20855, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/RWCY.2000.14002.
SUMMARY Alternative names
The cell surface receptor for IL-4 is composed of two Initially, the term IL-4R was used to describe the
polypeptide proteins that span the plasma mem- receptorforIL-4,butin1993itbecameclearthattheIL-
branes. One of these proteins chains, the IL-4R(cid:11), 4receptorconsistsoftwoseparatechains(Russelletal.,
bindstoIL-4withhighaffinity.BindingofIL-4tothe 1993):the140kDaIL-4-bindingchainandthecommon
IL-4R(cid:11) on the cell surface results in its association gamma chain, (cid:13)c (Figure 1). The 140kDa chain was
with a second protein. In the type I IL-4 receptor thentermedtheIL-4R(cid:11),althoughothergroupsinitially
complextheassociatingchainisthecommon(cid:13) chain. referred to it as the IL-4R(cid:12) due to its analogy to the
InthetypeIIIL-4receptorcomplexitistheIL-13R(cid:11) IL-2R(cid:12)chain.Numerousstudiessuggestedarelation-
chain. Over the last 8 years, much work has focused shipbetweenthereceptorforIL-4andthereceptorfor
on understanding the discrete signal transduction IL-13(Callardetal.,1996;Murataetal.,1998).Oneof
pathways activated by the IL-4 receptor and the these ligands could suppress the binding of the other
coordination of these individual pathways in the to cells capable of responding to both cytokines.
regulation ofa finalbiological outcome.Experiments
focused on signaling pathways have delineated the
mechanism by which IL-4 regulates cell growth,
Figure1 IL-4receptorcomplexes.ThetypeIIL-4
survival, and gene expression. Strategies to block
receptor complex comprises the IL-4-binding chain
binding of IL-4 to its receptor and to target specific termed the IL-4R(cid:11). The binding of IL-4 to this
signaling pathways are being tested to treat diseases chainallowsheterodimerizationwiththecommon(cid:13)
associated with IL-4 such as allergy. chain called the (cid:13)c. The type II IL-4 receptor
complex consists of the IL-4R(cid:11) chain and the IL-
13R(cid:11)1. The IL-4R(cid:11) is associated with the tyrosine
BACKGROUND kinase JAK1. The (cid:13)c is associated with the JAK3
while theIL-13R(cid:11)1probablyassociates witheither
Discovery JAK2 or TYK2, but not JAK3.
The structure of the IL-4 receptor complex was first Type I Type II
discoveredusingchemicalcrosslinkingof[125I]IL-4to
molecules on the surface of IL-4-responsive cells
(Ohara and Paul, 1987). Generally, two major g c IL-13Ra 1
complexes were found crosslinked to [125I]IL-4. One
contained [125I]IL-4 bound to a protein of (cid:24)140kDa;
JAK2
the second variably contained 80 and 70kDa JAK1 JAK3 JAK1JAK? TYK2
molecules crosslinked to [125I]IL-4, depending on the
typeofcellusedforanalysis.Subsequently,8yearsof
study revealed the complex nature of the IL-4
receptor. IL-4Ra IL-4Ra
1472 Achsah D. Keegan
Additionally, a mutant form of human IL-4 in which into a helper phenotype called TH2. In addition, it
Tyr124 has been replaced by Asp (Y124D), that is playsamajorroleinclassswitchingtoIgG1andIgE.
capableofbindingtothehumanIL-4receptorwithhigh However,sincetheIL-4R(cid:11)chainisusedasareceptor
affinitybutfailstosignalanIL-4-specificresponse,is component by both IL-4 and IL-13 (Callard et al.,
abletoantagonizecompetitivelybothIL-4-andIL-13- 1996), its loss results in more severe defects than the
induced proliferation. Recent analysis of the IL-13 loss of IL-4 alone.
receptor structure indicates that a functional IL-4
receptorcomplexcanalsobecomprisedoftheIL-4R(cid:11)
chainandtheIL-13R(cid:11)chain(Hiltonetal.,1996).The
GENE
complex containing the IL-4R(cid:11) and the (cid:13)c is called
thetypeIIL-4receptor.TheIL-4receptorcontaining
Accession numbers
the IL-13R(cid:11) is termed type II (Callard et al., 1996)
(Figure1).
ThegeneencodingthemouseIL-4R(cid:11)hasbeencharac-
terizedindetail(Wrightonetal.,1992)(Figure2).The
Structure
mouse IL-4R(cid:11) gene is located on chromosome 7 and
the human IL-4R(cid:11) gene is localized on chromosome
As shown in Figure 1, there are two types of IL-4 16. In addition, cDNA encoding the human, mouse,
receptor complexes. These are thought to function as andratIL-4R(cid:11)havebeencloned(accessionnumbers:
heterodimers. The type I receptor consists of the IL- human X52425, mouse M29854, rat X69903).
4R(cid:11) and the (cid:13)c, while the type II receptor consists of
theIL-4R(cid:11)andtheIL-13R(cid:11).ThetypeIreceptorisa
structure specific for IL-4 (Russell et al., 1993). Sequence
However,thestructurethatmakesupthetypeIIIL-4
receptorcanactasareceptorcomplexforIL-4orIL-
ThemouseIL-4R(cid:11)isencodedby12exons(accession
13 (Callard et al., 1996). The IL-4R(cid:11) has affinity for
numbers:M64868,M64869,M64870,M64871,M64872,
IL-4butnotforIL-13,whiletheIL-13R(cid:11)hasaffinity M64873,M64874,M64875,M64876,M64877,M64878,
forIL-13butnotforIL-4.Thebindingofligandwith M64879) (Figure 2). Exons 1–2 make up the 50
the appropriate chain induces dimerization with the untranslatedregion.Exon3encodesthesignalpeptide
other chain. Studies using engineered chimeric
which is comprised of (cid:24)25 amino acids. Exons 4–7
receptor complexes have indicated that homodimers
encode the extracellular domain which contains the
of the cytoplasmic region of the IL-4R(cid:11) can mediate
cysteinepairsandWSXWSmotifthatarethehallmark
IL-4-specific responses (for example, see Fujiwara
signsofthehematopoieticreceptorsuperfamily.Exon8
et al., 1997). It is not yet clear whether a full-length
codes for the C-terminus of the soluble form of the
IL-4R(cid:11) ever signals as a homodimer naturally. mouseIL-4R(cid:11).Inthecellsurfaceform,exon8isspliced
out,leavingexons7and9adjoining.Exon9encodesthe
Main activities and transmembrane region. Exon 8 contains a 114 bp
sequencethatencodessixnovelaminoacidsfollowedby
pathophysiological roles
astopcodon.Thissequenceisinsertedjustpriortothe
endoftheextracellulardomainbyalternativesplicing
ThemainactivitiesoftheIL-4receptorareveryclosely ofthemRNAandresultsintheproductionofa40kDa
linked to the major activities of IL-4. As the receptor soluble receptor with a C-terminus that is not found
for IL-4, it plays a large role in the regulation of the in the full-length IL-4R(cid:11). Exons 10–12 encode the
differentiation of naive CD4+ T cells, driving them cytoplasmic region. While soluble IL-4R(cid:11) capable of
Figure2 ThemouseIL-4R(cid:11)gene.ThegeneencodingmouseIL-4R(cid:11)contains12exonsand11
introns. Exons1and2codefor the50 untranslatedregion (50 UT). Exon3codesfor thesignal
peptide (Sig). Exons 4–7 encode the extracellular domain. Exon 8 codes for the carboxy tail of
thesolubleversionoftheIL-4R(cid:11)(Sol)andcontainsatranslationalstop,whileexon9contains
the transmembrane domain (TM). Exons 10–12 encode the cytoplasmic domain.
5'UT Sig Extracellular Sol TM Cytoplasmic
1 2 3 4 5 6 7 8 9 10 11
WSX
CC CC
WS
IL-4 Receptor 1473
bindinghumanIL-4withhighaffinityhasbeenfoundin LoopsinD1 (L1,L2, and L3)andloopsin D2 (L5
theserumofhumans,itisthoughtthatitoriginatesfrom and L6) make contacts with helices A and C in IL-4.
proteolytic cleavage of the full-length receptor rather Interestingly, IL-4 bound to the IL-4BP shows small
thanfromalternativesplicing. changesinitsstructure,especiallyinhelicesAandD.
Interestingly, both the (cid:13)c and the IL-13R(cid:11) chains The changes are localized to regions implicated in
are localized to the X chromosome. Both are also binding to the (cid:13)c, suggesting that binding of IL-4 to
members of the hematopoietin receptor superfamily. the IL-4R(cid:11) creates the (cid:13)c-binding epitope.
The cytoplasmic domain of the human IL-4R(cid:11)
contains more than 550 amino acids. There are no
PROTEIN
consensussequencescharacteristicofserine/threonine
or tyrosine kinases. The cytoplasmic region contains
Accession numbers twoacidicregionsandisgenerallyserine-andproline-
rich.ThereisaBox-1sequenceclosetothetransmem-
Theaminoacidsequencesforthehuman,mouse,and braneregion,originallydescribedinthegp130chainof
rat IL-4R(cid:11) can be found in the SwissProt database. the IL-6 receptor that is shared among many of the
Accession numbers for the protein sequence are hematopoietinreceptorfamilymembers.Therearefive
human A60386, mouse AAA39299, and rat S31575. tyrosineresiduesinthecytoplasmicregionwhosesur-
rounding amino acid sequences are highly conserved
amongtherat,mouse,andhumanIL-4R(cid:11)(Figure3).
Description of protein
Thishighdegreeofhomologybetweenthespeciessug-
gests some functional importance for these residues
The IL-4R(cid:11) is a transmembrane protein of greater thathasbeenborneoutbymutagenesisstudies.
than 800 amino acids including its leader sequence.
For the human IL-4R(cid:11), there are a total of 825
Relevant homologies and
amino acids with the first 25 comprising the leader
sequence. The extracellular domain consists of (cid:24)220 species differences
amino acids. There are five potential N-linked
glycosylation sites in the extracellular region, and
Human,mouse,andratIL-4R(cid:11)aregenerallysimilar,
biochemical studies suggest that about three are in
withvirtually90–100%identityinkeysequencemotifs
fact glycosylated (for reviews see Nelms et al., 1999
and Keegan et al., 1996).
Figure 3 Conserved cytoplasmic tyro-
TheextracellulardomainoftheIL-4R(cid:11)(termedIL-
sineresidues.Thecytoplasmicdomainsof
4BP) has been co-crystallized with IL-4 (Hage et al.,
the rat, mouse, and human IL-4R(cid:11)
1999). The coordinates for this structure have been
contain five tyrosines whose surrounding
deposited in the Protein Data Bank under the code sequencesarehighlyconserved.Theseare
1IAR.Thisanalysisshowsthattheextracellularregion numbered 1–5 starting with the most
is comprised of two domains arranged in an L shape. membrane-proximal tyrosine.
Both domains are related to the fibronectin type III
domain. Both domains contain seven antiparallel (cid:12)
hu 488 PLViagNPAYRSFSnsl
strands separated by loops and an occasional short
Y1 mu 491 PLViadNPAYRSFSdcc
helix.TheN-terminaldomain(D1)liesabout45degrees
rt 491 PLVisdNPAYRSFSdfs
fromhorizontal.Itconsistsofaminoacids1–91andis
arrangedinanH-typesubclassoftheIg-typefold.D1
hu 570 APtsGYQEFVhAVeQG
contains three pairs of cysteine residues engaged in Y2 mu 570 APagGYQEFVqAVkQG
disulfidebonding(Cys9–Cys19,Cys29–Cys59,Cys49– rt 570 APtsGYQEFVqAVkQG
Cys61).Thefirsttwopairsarecharacteristicofmembers
of the type I cytokine or hematopoietin receptor hu 597 PpGeaGYKAFSSLLaS
superfamily.ThethirdpairappearsnoveltotheIL-4BP. Y3 mu 597 PsGdpGYKAFSSLLsS
Thedomainclosesttothetransmembraneregion(D2)is rt 597 PsGdtGYKAFSSLLsS
arrangedinanS-typefibronectintypeIIIdomainina
hu 627 GeeGYKPFQdli
verticalorientation.TheD1andD2domainsareclose
Y4 mu 627 GhgGYKPFQ---
toperpendiculartooneanother.D2doesnotcontain
rt 627 GcgGYKPFQnpv
any disulfide bonds, but does contain the WSXWS
motif prior to the (cid:12)G strand. The WSXWS sequence
hu 705 DsLGsGIVYSaLTCH
helpsto maintain properfolding and transportto the Y5 mu 701 DdLGfGIVYSsLTCH
cellsurface. rt 701 DdLGlGIVYSsLTCH
1474 Achsah D. Keegan
and modules (Figure 3). Overall amino acid identity lymphocytes (Huang et al., 1999), although the
between the human and mouse is 48%, between mechanism by which this might occur is not clear.
humanandratis 46%,andbetweenratandmouse is Treatmentofpatientswithsteroidshasbeenshownto
72%. The extracellular domain of the IL-4R(cid:11) shows diminish IL-4R(cid:11) expression (Wright et al., 1999).
between 20% and 30% homology to a number of
other cytokine receptor family members. Release of soluble receptors
Affinity for ligand(s)
In the murine system, soluble receptors capable of
binding IL-4 with high affinity can arise by
IL-4 binds to its receptor with high affinity. Binding alternative splicing of the mRNA (Wrighton et al.,
sites for [125I]IL-4 with K values of 20–300pM have 1992).Thesolubleformcontainsnovelaminoacidsat
d
been detected on many hematopoietic and nonhema- the C-terminus. Evidence for alternative splicing has
topoieticcelltypes(OharaandPaul,1987;Lowenthal not been provided for the human IL-4R(cid:11). Since
etal.,1988).Thenumberofreceptorsexpressedonthe soluble receptors for IL-4 have been found in human
surfacesofcellsisgenerallyquitelow,rangingfrom50 sera,itislikelytheyarisebyaproteolyticmechanism.
to 5000 sites per cell. The IL-4R(cid:11) contains the vast
majority of binding affinity for IL-4. The soluble
SIGNAL TRANSDUCTION
versionoftheIL-4R(cid:11)canbindIL-4withhighaffinity
also. The additional contribution of the (cid:13)c to cell
surface binding affinity has been estimated at 3-fold SeveralcomprehensivereviewsonsignalingbytheIL-
(Russelletal.,1993)whilethecontributionoftheIL- 4 receptor have been published and provide detailed
13R(cid:11)hasbeenestimatedtobebetween5-and10-fold discussion of the experimental data and extensive
(Hilton et al., 1996). referencessupportingthecurrentmodelofsignaltrans-
duction (Figure 4) (see Wang et al., 1995; Keegan
et al., 1996; Nelms et al., 1999).
Cell types and tissues expressing
the receptor
Associated or intrinsic kinases
Thevastmajorityofcelltypesinthebodyexpressoneor
Althoughthereisnointrinsicenzymeactivityencoded
theother(orboth)oftheIL-4receptorcomplexes.IL-4
in the IL-4R(cid:11), treatment of cells with IL-4 activates
receptors have been identified on most cells of
cytoplasmictyrosinekinases(Ihle,1995;Johnstonetal.,
hematopoieticorigin,cellsofthebrain,muscle,kidney,
1996).TheJanusfamilyoftyrosinekinases(JAKs)are
and placenta, and in primary cell types including
constitutivelyassociatedwiththeIL-4receptor.JAK1is
fibroblasts, epithelial cells, endothelial cells, and a
associatedwithIL-4R(cid:11)whileJAK3iscoupledtothe(cid:13)c
number of different tumors, as well as many others
(Figure1).TheassociationoftheJAK1kinasetotheIL-
(OharaandPaul,1987;Lowenthaletal.,1988;Doucetet
4R(cid:11) is thought to be via the conserved Box-1 site.
al., 1998; Dubois et al., 1998; Henriques et al., 1998;
Mutation of this site or mutation of JAK1 itself
Kotsimbosetal.,1998;Mehrotraetal.,1998;vander
abolishes all functional activity of the IL-4 receptor.
Veldenetal.,1998).
BothJAK1andJAK3becometyrosinephosphorylated
upon treatment of hematopoietic cells with IL-4. IL-
Regulation of receptor expression
13R(cid:11) does not associate with JAK3. However, it
associateswitheitherJAK2orTYK2dependingonthe
There is not much information available on the celltype,andthesekinasescanbetyrosinephosphory-
regulation of expression of IL-4 receptor complexes. lated in response to IL-4 in some cell types (Murata
All components are expressed to some degree on et al., 1998). Heterodimerization of the receptor sub-
resting cells. Stimulation of lymphocytes through the unitsisthoughttoactivatethekinasesandinitiatethe
antigen receptor results in the increase of IL-4R(cid:11) signalingcascade(Figure4).
expression (Ohara and Paul, 1988). Polyclonal IL-4is abletosignalincells expressingtheIL-4R(cid:11)
activators such as LPS also induce expression. andeitherthe(cid:13)cortheIL-13R(cid:11).IL-4treatmentisable
Interestingly, IL-4 itself acts to regulate the levels of toinducethetyrosinephosphorylationofatranscrip-
expression of IL-4R(cid:11). Preliminary studies in mice tion factor (STAT6) in cell lines derived from severe
lacking expression of the active tyrosine phosphatase combined immunodeficiency (SCID) patients lacking
SHP-1 indicate that this phosphatase may also play the (cid:13)c or JAK3, albeit less efficiently than in normal
some role in regulating the expression of IL-4R(cid:11) in cells.Therefore,intheabsenceof(cid:13)c,orintheabsenceof
IL-4 Receptor 1475
Figure 4 Signaling by the IL-4 receptor. Several of the IL-4-activated
signaltransductionpathwaysareshownindiagramform.Thebindingof
IL-4 to the IL-4R(cid:11) induces heterodimerization with the (cid:13)c (shown)
or the IL-13R(cid:11)1. The dimerization activates the Janus kinases that
initiate the phosphorylation cascade. Tyrosine residues in the cytoplas-
mic tail of the IL-4R(cid:11) become phosphorylated and act as docking sites
for signaling molecules. The first cytoplasmic tyrosine residue (Y1,
green) is in a sequence motif called the I4R-motif that interacts with
protein tyrosine-binding domains (PTB). Members of the insulin
receptor substrate family (IRS) and Shc dock to this site. Tyrosine
residues2–4(orange)interactwiththeSH2-domainofSTAT6.Thefifth
cytoplasmic residue (red) lies in a consensus motif termed an ITIM
shown in other receptors to dock the SH2-domains of tyrosine
phosphatases. After being recruited to the receptor complex, these
signaling molecules are tyrosine phosphorylated. Phosphorylated
STAT6 (green) dimerizes, migrates to the nucleus, and binds to
promoters of genes such as CD23 and MHC class II. Phosphorylated
IRS(darkblue)bindstothep85subunitofPI-3kinase(lightblue)and
to GRB2 (orange). The IRS pathway has been linked to cellular
proliferationinresponsetoIL-4.TheactivatedPI-3kinaseregulatesthe
p70S6 kinase and akt, both of which have been shown to participate in
antiapoptosis. PI-3 kinase activity also regulates the IL-4-induced
phosphorylation of the DNA-binding protein HMGI(Y). (Full colour
figure may be viewed online.)
IL-4
g c IL-4Ra
Cell membrane
JAK3 JAK1
IRS-1/2
STAT6 Y
Y
Y
Y GRB2 p70S6K PKB
Y Shc GROWTH
PATHWAY
Anti-apoptotic
HMGI(Y) pathway
G1 Cell
M S cycle
Nucleus G2
IL-4 responsive genes
l-c
MHC class II
CD23
IL-4Ra
the kinase to which (cid:13)c associates, IL-4 signaling can STAT6, that is a member of the signal transducers
occur via the type II IL-4 receptor (Johnston et al., and activators of transcription (STAT) family (Ihle,
1996). 1995). STAT6 is recruited to the IL-4R(cid:11) by binding
Another tyrosine kinase that interacts with the to the second, third, or fourth cytoplasmic tyrosine
IL-4R(cid:11) is c-fes. The importance of c-fes in IL-4 residues via its SH2 domain after they become phos-
signalingisnotclear,butsomeevidencesuggeststhat phorylated (Figure 3). STAT6 then becomes tyrosine
it may regulate growth and production of IgE in phosphorylated, dimerizes, migrates to the nucleus,
response to IL-4. and binds to consensus sequences found within
promoters of IL-4-regulated genes. This factor plays
amajorroleingeneregulationandinmanyaspectsof
Cytoplasmic signaling cascades
the allergic response including TH2 differentiation,
IgE production (reviewed in Nelms et al., 1999) and
One of the signaling pathways initiated by IL-4 is in models of allergic lung inflammation (Kuperman
a latent cytoplasmic transcription factor, termed et al., 1998).
1476 Achsah D. Keegan
A second signaling pathway activated by the IL-4 IRS1andIRS2havebeenshowntosignalsimilarly.
receptor is the insulin receptor substrate (IRS) family However,therearesomedifferencesinthespectrumof
(IRS-1, IRS-2, IRS-3, and IRS-4) pathway (White, proteinsrecruitedtoIRS1andIRS2.Themechanismof
1998). These proteins are large cytoplasmic docking these differences and their significance are not clear.
proteinswhichcontainaproteintyrosinebinding(PTB) MostcellsofhematopoieticoriginexpressIRS2,butnot
domain and many sites for serine/threonine and IRS1,whereasothercelltypesmayexpresseitheroneor
tyrosine phosphorylation. The IRS proteins are bothofthesefamilymembers.Humanthymocytesand
recruitedtotheIL-4R(cid:11)bythefirstcytoplasmictyrosine peripheral T cells express both. It is possible that the
residue (Tyr1) that lies within a consensus motif also activation of IRS1 or IRS2 by IL-4 may have subtle
found in receptors for insulin and the insulin-like consequences for downstream signaling pathways.
growth factor type I (IGF-1) called the I4R motif Very few studies have yet examined the function
(Figure3).ThePTBdomainoftheIRSproteininter- of IRS3 or IRS4 in IL-4 signaling. The role of the
acts directly with the I4R-motif of the IL-4R(cid:11). The IRSfamilymembersinIL-4signalingwillprobablybe
structure of this interaction has been solved (Zhou complex.
etal.,1996)andcanbeobservedbygoingtothemolec- IL-4 signaling also results in the tyrosine phoshor-
ular modeling database of the National Center for ylation of Shc. Shc contains a PTB domain and is
Biotechnology Information (www.ncbi.nlm.nih.gov/ recruited to the IL-4R(cid:11) by the I4R motif. The
Structure) and searching for the identifier 5977. The importanceofShcinIL-4signalingis still unclear.In
ProteinDataBaseIDis1IRS. some cell types IL-4 does not induce the tyrosine
Tyrosine phosphorylated sites within the IRS pro- phosphorylation of Shc. However, IL-4 is able to
teins associate with cellular proteins that contain induce the tyrosine phosphorylation of Shc in mouse
SH2 domains. One signaling molecule with which all B cells. In addition, a cell line which is highly
IRS family members interact is the p85 subunit of responsive to IL-4 shows strong Shcphosphorylation
phosphatidylinositol 30-kinase (PI-3 kinase) (White, inresponsetoIL-4.ShcactsasanadapterforGRB2/
1998). Numerous studies have shown that the inter- SOS and functions to activate the Ras pathway. An
action of IRS proteins with the p85 subunit results in additional protein, FRIP-1, also binds to the I4R
theactivationofthep110catalyticsubunitofthePI-3 motif via its PTB domain. FRIP is tyrosine
kinaseenzyme.ActivePI-3kinasecatalyzesthetrans- phosphorylated in response to IL-4, interacts with
fer of phosphate from ATP to the D3 position of RasGAP, and therefore is thought to inactivate the
the inositol ring in membrane-bound phosphatidy- Ras pathway (Nelms et al., 1999). The delineation of
linositol.PI-3kinaseactivityisimportantforgrowth, the contribution of these molecules in mediating IL-4
survival,andregulationofgeneexpressioninresponse responses will require further study.
toIL-4.Severalsignalingmoleculeswhoseactivitiesare The C-terminus of the IL-4R(cid:11) contains the fifth
downstream of PI-3 kinase activity have been impli- conserved cytoplasmic tyrosine residue (Figure 3),
catedinIL-4responses,includingp70S6kinase,theAkt which lies in a consensus motif termed an ITIM
kinase,andthenonhistonehigh-mobilitygroupDNA- (immunoreceptor tyrosine-based inhibitory motif).
binding protein HMGI(Y) (for literature review, see This sequence (Muta et al., 1994) was identified in
Nelmsetal.,1999)(Figure4). negative signaling receptors and has been shown to
Other signaling molecules that have been shown to bind to the SH2 domains of the tyrosine and lipid
interact with IRS family members are the growth phosphatases, SHP-1 and SHIP. While binding of
factorreceptor-boundprotein2(GRB2),theSH2and SHP-1toaphosphopeptidederived from theIL-4R(cid:11)
SH3 domain containing adapter protein nck, the src- ITIM sequence has been demonstrated, it is not yet
family kinase fyn, and the src-homology protein clear whether SHP-1 or SHIP actually dock to this
tyrosine phosphatase 2. The importance of these site of the IL-4R(cid:11) in cells.
other interactions in mediating IL-4 responses is not
clear. GRB2 is constitutively associated with the
guaninenucleotideexchangefactorcalledSOSwhose
primary function is to catalyze exchange of GDP DOWNSTREAM GENE
bound to Ras with GTP. The GTP–Ras complex is
ACTIVATION
active and results in the activation of the Raf kinase
and MAP kinases. Although it has been clearly
Transcription factors activated
demonstrated that IL-4 induces the association of
GRB2 with IRS, it has been more difficult to
demonstrate any IL-4-induced activation of the Ras/ Two different types of transcription factors are
Raf/MAP pathway. activated by IL-4. STAT6 is directly recruited and
IL-4 Receptor 1477
activated by binding to phosphorylated tyrosine BIOLOGICAL CONSEQUENCES
residues found in the cytoplasmic domain of the IL-
OF ACTIVATING OR INHIBITING
4R(cid:11). As discussed above, STAT6 becomes tyrosine
RECEPTOR AND
phosphorylated itself, dimerizes, migrates to the
nucleus, and binds to DNA sequences found in the PATHOPHYSIOLOGY
promoterelementsofIL-4-responsivegenes(reviewed
in Nelms et al., 1999). IL-4 also activates the small, Unique biological effects of
nonhistone chromosomal protein HMGI(Y) by
activating the receptors
inducing its serine phosphorylation in an IRS-
dependent manner (Wang et al., 1997). The serine
phosphorylation of HMGI(Y) in response to IL-4 Unique biological effects of activating the IL-4
also depends on PI-3 kinase and p70S6 kinase. receptor are similar to the unique responses to IL-4.
TheseincludethedifferentiationofTcellstotheTH2
type and immunoglobulin class switching to IgE. In
addition, activating the receptor by administration of
Genes induced
IL-4 or IL-13 directly into the lungs elicits symptoms
of asthma including eosinophilia, mucus production,
Signaling by the IL-4 receptor complex results in the andairwayhyperresponsiveness(Grunigetal.,1998).
regulation of a number of genes. Many, but not all, Thereis evidencetosupportthenotionthatsignaling
are regulated by the activation of STAT6. IL-4 alone through the IL-4R(cid:11) chain by IL-4 or IL-13 can
can induce/enhance the expression of CD23, MHC directly induce mucus secretion by goblet cells and
class II, and IL-4R(cid:11). In the presence of some other eotaxinreleasebylungepithelialcells(Dabbaghetal.,
stimulus such as LPS, TNF, or antigen receptor 1999; Li et al., 1999).
stimulation, IL-4 induces/enhances expression of the
germline transcripts for the heavy chain of IgG1
Phenotypes of receptor knockouts
(G(cid:13)1) and IgE (G"), VCAM-1, and Bcl-xL. In
STAT6 knockout mice, IL-4 is not able to regulate and receptor overexpression mice
expression of CD23, MHC class II, IL-4R(cid:11), G(cid:13)1 or
G" (Nelms et al., 1999). However, induction of In general terms, the IL-4R(cid:11) knockout mice are
VCAM-1 by IL-4 is maintained (Kuperman et al., similar to the IL-4 knockout mice. They are TH2
1998). deficient and have reduced IgE responses (Noben-
Trauth et al., 1997). However, the IL-4R(cid:11) knockout
mice are unable to expel the gastrointestinal
nematode parasite Nippostrongylus brasiliensis, while
Promoter regions involved
this parasite is expelled in IL-4 knockout mice
(Barneretal.,1998;Urbanetal.,1998).Theseresults
The promoters of several IL-4-responsive genes have indicatethatIL-13signalingthroughtheIL-4R(cid:11)may
been characterized. These promoters (promoters for be critical for nematode expulsion. Interestingly, IL-
CD23, IL-4R(cid:11), G(cid:13)1, G") have in common the 4R(cid:11) knockout mice have greatly reduced asthma-like
presence of a sequence motif specific for STAT6 symptoms in response to allergen, even when TH2
binding termed as N4-GAS (TTCXXXXGAA). cells are provided exogenously (Grunig et al., 1998).
Interestingly, the promoter for IL-4 also contains a These results suggest that IL-4R(cid:11) on lung-derived
STAT6 consensus-binding site although it is not cells other than T cells is important in the
thought to playa major role in the induction of tran- development of asthma pathology. There are no IL-
scription of IL-4 in vivo. Although the IL-4-activated 4R(cid:11) overexpressing mice.
STAT6 is clearly important in the regulation of
transcription of these genes, other transcription fac-
Human abnormalities
torscooperatetofullyregulateexpression.Inthecase
of the promoter for G", the factors STAT6, NF(cid:20)B,
cEBP, and BSAP cooperate to positively regulate The important role that IL-4 and IL-13 play in the
transcription (Delphin and Stavnezer, 1995). Addi- regulation of T cell responses and IgE production
tionally, the IL-4-induced serine phosphorylation of logically suggest that the IL-4R(cid:11) may play a role in
HMGI(Y) results in the de-repression of the G" human disease. This idea is supported by the finding
promoter, resulting in the enhancement of transcrip- that the region of human chromosome 16 contain-
tion (Kim et al., 1995). ing the IL-4R(cid:11) is associated with human allergy
1478 Achsah D. Keegan
(Deichmann et al., 1998). There are naturally and IgG4 production by peripheral blood mononuclear
frequently occurring polymorphisms in both the cells isolated from hyper-IgE syndrome patients
human and mouse IL-4R(cid:11) (Schulte et al., 1997; (Garraoud et al., 1999). In mouse models, treatment
Hershey et al., 1997; Mitsuyasu et al., 1998). Several with the anti-IL-4R(cid:11) monoclonal (M1) has many of
of these polymorphisms have been associated with thesameeffectsasanti-IL-4antibodytreatmentoras
atopyinhumans,althoughthereiscontroversyinthis those observed in the IL-4 knockout mice. These
field. One group has found an association between a include inhibition of TH2 differentiation and IgE
Val50toIlechangeintheextracellulardomainofthe production. In some cases, injecting mice with IL-4–
IL-4R(cid:11) in their patient population (Mitsuyasu et al., M1 complexes increases the bioavailability of IL-4
1998). An association between a Gln576 to Arg since it increases the serum half-life.
change(Figure3)andallergyinUSpatientshasbeen
found(Hersheyetal.,1997),butotherstudiesdidnot
find a correlation between this polymorphism and References
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1480 Achsah D. Keegan
LICENSED PRODUCTS Monoclonal antibody to human and mouse
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