IL-18 Receptor

6 Pages·0.072 MB·English

by  Okamura H., Tsutsui H., Kashiwamura S.-I.

IL-18 Receptor
Haruki Okamura*, Hiroko Tsutsui, Sin-ichiro Kashiwamura,
Tomohiro Yoshimoto and Kenji Nakanishi
Hyogo College of Medicine, Nishinomiya, Japan
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.15002.
SUMMARY family (Parnet et al., 1996). A novel member of the
IL-1R family, with the highly conserved IL-1R hall-
markdomains,wasrecentlycloned(Bornetal.,1998).
Much interest has been focused on the proinflamma-
Based on its homology to IL-1R accessory protein
tory cytokines, such as TNF(cid:11), IL-1(cid:11), IL-1(cid:12), and IL-
(AcP), it is termed as an IL-1R AcP-like protein
18, because these cytokines have critical roles in the
(AcPL). Like IL-1R AcP, which does not directly
immune and inflammatory reactions. Of these cyto-
bindtoIL-1butstabilizesIL-1Rconformation,AcPL
kines, IL-1 and IL-18 have common structural fea-
as well as IL-1Rrp is required to mediate signaling
tures,andindeed,theirreceptorsformafamily.They
by IL-18. Recently, a soluble IL-18-binding protein
also share parts of a common signal transducing
(IL-18BP) has also been cloned (Novick et al., 1999).
system, comprising IL-1 receptor-associated kinase
This protein was purified from human urine by
(IRAK), MyD88, and TNF receptor-associated
chromatography of IL-18 beads, sequenced, and
factor (TRAF-6), and activation of the transcription
cloned. IL-18BP directly binds to IL-18 and inhibits
factor NF(cid:20)B. Although IL-1R type I and IL-18R(cid:11)
the IFN(cid:13)-inducing action of IL-18.
(IL-1Rrp) have a high homology, the receptors for
eachcytokineareexpressedondifferenttypesofcells.
For example, expression of IL-18R(cid:11) (IL-18R), but Alternative names
notIL-1RtypeI,onTcellsisupregulatedbyIL-12,a
powerful differentiation factor for TH1. IL-18R(cid:11) is The IL-18-binding component of IL-18R has been
now accepted as one of the surface markers for TH1 identified as IL-1Rrp (Parnet et al., 1996; Torigoe
cells. IL-18, like IL-1, is expressed in a variety of et al., 1997). It was proposed that IL-18, once
tissuesotherthanimmuneorgans,andtheexpression designated as an IFN(cid:13)-inducing factor (IGIF), might
of IL-18R in these tissues needs to be examined in be renamed as IL-1(cid:13) because of its similarities in
relationship to its pathophysiological roles. secondary structure to IL-1 and because, like IL-1, it
lacksasignalpeptideinitssequence.However,IL-1(cid:11)
and IL-1(cid:12) utilize the same receptor, whereas IL-18
BACKGROUND does not bind to or share their receptor. Therefore, it
seemsbettertocallIL-1RrptheIL-18receptor.There
Discovery isalsoaproposalthatIL-1Rrpshouldberenamedas
IL-18R(cid:11) and AcPL as IL-18R(cid:12), but general
agreement on this has not been attained.
Human IL-18 receptor has been purified and char-
acterized using monoclonal antibody which specifi-
Structure
cally inhibits the binding of IL-18 to Hodgkin’s
diseasecelllineandinhibitsitsactions(Torigoeetal.,
1997). Its amino acid sequence completely matched The IL-1 receptor consists of an IL-1-binding com-
that of human IL-1 receptor-related protein (IL- ponent, IL-1R type I, and IL-1 signaling component,
1Rrp), whose DNA sequence had been published as IL-1R accessory protein (AcP). Similarly, the IL-18
an orphan receptor belonging to the IL-1 receptor receptor is composed of a ligand-binding subunit
1606 Haruki Okamura et al.
(IL-18R(cid:11)/IL-1Rrp) and a signaling component sequence. It is related to murine accessory protein
(IL-18R(cid:12)/AcPL). (31% homology), to murine T1/ST2 (30% homol-
ogy), and to murine IL-1R type I (27% homology).
Main activities and The cytoplasmic domains have slightly greater
sequence homology (36–44%) than the extracellular
pathophysiological roles
portions (20–27%) (Parnet et al., 1996).
Human and murine AcPL share 65% identity.
IL-18R mediates the signal of IL-18 and activates AcPL showshomologyof 25% toIL-1R typeI, 27%
signal-transducing molecules such as IRAK and to IL-1 AcP, and 26% to IL-18R (IL-1Rrp), respect-
TRAF-6, resulting in the translocation of NF(cid:20)B to ively (Born et al., 1998).
the nucleus. The pathophysiological roles of IL-18 Murine IL-18BP is 65.7% identical at the amino
remain to be clarified. Since IL-18R is expressed on acid level to human IL-18BP. There is no apparent
TH1 cells, but not on TH2 cells (Yoshimoto et al., homology with any other cytokine or cytokine recep-
1998;Xuet al.,1998),IL-18Rmaybean indicatorof tor, when examined by the homology research. Yet,
TH1 and be concerned with TH1-dominant tissue the Ig domain of IL-18BP is homologous to the third
injury (Rothe et al., 1997). Ig domain of IL-1R type II. In addition, IL-18BP is
significantly homologous to the putative proteins
encoded by several pox viruses (Novick et al., 1999).
GENE
Accession numbers Affinity for ligand(s)
GenBank: Scatchard plot analysis on the affinity of IL-18
Human IL-18R(cid:11) (IL-1Rrp): U43672 binding to L428 (human Hodgkin’s disease cell line)
Murine IL-18R(cid:11) (IL-1Rrp): U43673 suggested a single class of binding site for IL-18 on
Human IL-18R(cid:12) (AcPL): AF077346 these cells. The apparent K value was 18.5nM with
d
Murine IL-18R(cid:12) (AcPL): AF077347 18,000bindingsites/cells(Torigoeetal.,1997).COS-1
Human IL-18BP (IL-18-binding protein): AF110799 cells transfected with hIL-1Rrp cDNA express low-
Murine IL-18BP: AA498857 affinity hIL-18R (49,000/cell, K 46nM) by the same
d
analysis using [125I]hIL-18, indicating that IL-18R is
composed of IL-18R(cid:11)/IL-1Rrp. Although IL-18R(cid:12)/
Sequence: Chromosome location
AcPLdoesnotbindtoIL-18directly,coexpressionof
and linkages
IL-18R(cid:11)/IL-1Rrp and IL-18R(cid:12)/AcPL is required for
IL-18 responsiveness in terms of NF(cid:20)B activation
Human IL-18R(cid:11) (IL-1Rrp) maps to chromosome and c-Jun N-terminal kinase (JNK) activation (Born
2q13-21,wheregenesencodingIL-1(cid:11),IL-1(cid:12),IL-1Ra, et al., 1998). Furthermore, IL-18R(cid:11)-deficient mice
andIL-1receptors(typeI,abindingcomponent,and reveal that IL-18R(cid:11) is an essential component of IL-
type II, a decoy receptor) are located (Nolan et al., 18R for both IL-18 binding and exertion of IL-18-
1998;Aizawaetal.,1999).Ontheotherhand,human induced signal transduction (Hoshino et al., 1999).
IL-18 maps to chromosome 11q22, closely linked to Splenocytes from IL-18R(cid:11)-deficient mice do not
DRD2. Therefore, the genes for the IL-18 ligand and produce IFN(cid:13) or upregulate NK cell functions in
the IL-18 receptor map to different chromosomes. response to IL-18. Neither do they bind to IL-18 or
ThegeneforIL-18BP,arecentlyclonedsolubleIL-18 cause activation of NF(cid:20)B or c-Jun-terminal kinase
decoy receptor, is localized on chromosome 11q13 afterstimulationwithIL-18.However,atthistime,it
(Novick et al., 1999). is uncertain whether high-affinity IL-18R is com-
posedofbothIL-18R(cid:11)/IL-1RrpandIL-18R(cid:12)/AcPL.
PROTEIN Cell types and tissues expressing
the receptor
Relevant homologies and species
differences
IL-18R(cid:11)/IL-1Rrp mRNA is detectable in various
organs of mice including thymus, spleen, liver, lung,
Murine IL-18R (IL-1Rrp) is homologous to human intestine, colon, placenta, prostate, and heart.
IL-18R (IL-1Rrp) by 65% in overall amino acid However, it is not detectable in the brain, kidney,
IL-18 Receptor 1607
skeletal muscle, and pancreas (Parnet et al., 1996). initial binding study is consistent with the presence
This is interesting because IL-18 mRNA is strongly of both high-affinity and low-affinity IL-18-binding
expressedinthepancreas,skeletalmuscle,andkidney, sites. Measurement of [125I]IL-18 bound to IL-12-
whereexpressionofIL-18R(cid:11)/IL-1RrpmRNAisvery stimulated T cells revealed that they express 405
low (Ushio et al., 1996). In addition to above organs, high-affinity IL-18R (K 430pM) and 5500 low-
d
weak expression of IL-18R(cid:11)/IL-1Rrp mRNA is also affinityIL-18R(K 31.4nM)oneachcell(Yoshimoto
d
observed in the testis and ovary. et al., 1998). While IL-18R on T cells was suggested
Thus, IL-18R(cid:11)/IL-1Rrp mRNA is widely distrib- to be induced by IL-12, that on NK cells was shown
uted, but not universally. However, it needs to be to be constitutively expressed (Kunikata et al., 1998;
considered whether the reported IL-18R(cid:11) mRNA Hyodo et al., 1999).
expression in these organs is due to the possible con-
tamination of blood cells. It is also important to
Release of soluble receptors
determinewhichcelltypesexpressIL-18RintheseIL-
18R(cid:11)-expressing tissues. This will help to elucidate
the physiological roles of IL-18 in these tissues, par- A soluble IL-18 receptor (an IL-18-binding protein:
ticularly in nonimmune organs. IL-18BP) was purified and characterized from
Theexpression patternofIL-18R(cid:12)/AcPLisclosely human urine (Novick et al., 1999) and from the
similartothatofIL-18R(cid:11)/IL-1Rrp.Itisexpressedin sera of the mice sequentially administered with
lung, spleen, leukocytes, and colon, but not detected Propionibacterium acnes and LPS (Aizawa et al.,
inheart,brain,kidney,andmuscle(Bornetal.,1998). 1999). IL-18BP (38kDa protein) is constitutively
Resting murine T cells express no IL-18R mRNA expressed in the spleen, and belongs to the immuno-
and protein, whereas T cells stimulated with IL-12 globulin superfamily. No exon coding for a trans-
alone or cultured with antigen plus IL-12 to induce membrane domain was found in an 8.3kb genomic
TH1 cells begin to express IL 18R(cid:11)/IL-1Rrp mRNA sequence. IL-18BP can bind to IL-18 in high affinity,
andprotein(Xuetal.,1998;Yoshimotoetal.,1998). suggesting that IL-18BP may physiologically play a
IL-18R(cid:11) is not expressed on TH2 cells. soluble decoy receptor, functionally similar to the
NK cells constitutively express IL-18R(cid:11), as well as membrane-associatedIL-1RtypeII.Indeed,IL-18BP
IL-12R(cid:12), and both IL-18 and IL-12 augment NK abolishes the induction of IFN(cid:13) production by IL-18
activity independently of each other (Hyodo et al., bothinvitroandinvivo.Nosignificanthomologywas
1999). However, as for induction of IFN(cid:13), stimula- foundbetweenIL-18BPandIL-18R(cid:11)/IL-1RrporIL-
tion of NK cells solely with IL-12 or IL-18 induces 18R(cid:12)/AcPL. However, the Ig domain of IL-18BP is
only a trace amount of IFN(cid:13), while the combined homologous to the third Ig domain of the decoy
stimulation induces several hundred-fold amount of receptor of IL-1, IL-1R type II (Novick et al., 1999).
IFN(cid:13). Interestingly, IL-18BP is highly homologous to
Although coexpression of IL-18R(cid:11)/IL-1Rrp and proteins derived from several Pox viruses (Novick
IL-18R(cid:12)/AcPL is required for signaling by IL-18 etal.,1999).Infact,Molluscumcontagiosumvirus,a
(Born et al., 1998), it remains to be clarified whether common human poxvirus, encodes a family of pro-
both IL-18R(cid:11) and IL-18R(cid:12) are expressed simulta- teins with homology to IL-18BP (Xiang and Moss,
neously on IL-18-responsive cells, such as TH1 cells 1999). The proteins in this family have high-affinity
and NK cells. binding activity to IL-18 and have capacity to inhibit
both IL-18 binding and IL-18-induced IFN(cid:13) produc-
tion. Since IL-18 plays an important role in host
Regulation of receptor expression
defense against viral infection, these proteins may act
as an important escape tool from attack by the host
IL-18,incombinationwithIL-12,inducesTH1clones immune system.
and T cells to produce IFN(cid:13) (Ahn et al., 1997;
Yoshimoto et al., 1998; Xu et al., 1998; Murphy,
SIGNAL TRANSDUCTION
1998).Naı¨veTcellsdonotproduceIFN(cid:13) inresponse
to IL-18. Murine T cells that had been stimulated
with IL-12 exhibit dose-dependent proliferation and All the member of IL-1R family are involved in the
IFN(cid:13) production in response to IL-18, suggesting response to infections, and their cytoplasmic regions
that IL-12 renders naı¨ve T cells responsive to IL-18 contain six distinct regions which are well conserved
through induction of IL-18R. T cells stimulated with (O’Neill andGreen,1998).Thesehomologiesseemto
IL-12 have the capacity to specifically bind IL-18. be important for interactions with signal transducing
The shape of the Scatchard plot obtained from our proteins. IL-18R does not activate the JAK/STAT
1608 Haruki Okamura et al.
signaling pathway, but it shares IL-1R-associated IL-12 and IFN-(cid:13)-inducing factor in enhanced production of
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Furthermore, IL-18-induced activation of NF(cid:20)B and Kanakaray, P., Ngo, K., Wu, Y., Angulo, A., Ghazal, P.,
c-Jun N-terminal kinase (JNK) is blocked in Harris, C. A., Siekierka, J. J., Peterson, P. A., and Fung-
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natural killer andT helpercell type1 responses inIL-1 recep-
have been shown to display an impaired response in
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their splenocytes to stimulation with IL-18 as well as
1129–1138.
IL-1 (Kanakaray et al., 1999; Thomas et al., 1999). Kojima, H., Takeuchi, M., Ohta, T., Nishida, Y., Arai, N.,
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seems to be a major signaling pathway for IL-18 as Interleukin-18 activates the IRAK-TRAF6 pathway in mouse
EL-4cells.Biochem.Biophys.Res.Commun.244,183–186.
wellasIL-1.IL-18hasalsobeensuggestedtodirectly
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There is a second signal pathway of IL-18. IL-18 variousperipheralbloodcellsubsetsasdeterminedbyanti-hIL-
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Matsumoto, S., Tuji-Takayama, K., Aizawa, Y., Koide, K.,
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Takeuchi, M., Ohta, T., and Kurimoto, M. (1997).
activated in TH1 cells stimulated with IL-18 (Tsuji-
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