IL-12 Receptor

8 Pages·0.082 MB·English

by  Esche C., Shurin M.R., Lotze M.T.

IL-12 Receptor
Clemens Esche, Michael R. Shurin and Michael T. Lotze*
Biological Therapeutics Program, University of Pittsburgh Cancer Institute,
Pittsburgh, PA 15213, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14006.
SUMMARY an additional (cid:12)-type IL-12R protein was identified
and designated IL-12R(cid:12)2 (Presky et al., 1996), while
thepreviouslyreportedsubunitwasreclassifiedasIL-
The functional high-affinity IL-12 receptor is com-
12R(cid:12)1 (Presky et al., 1996). A recent report suggests
posed of at least two (cid:12)-type receptor subunits, each
the existence of a third chain (Kawashima et al.,
independently exhibiting a low affinity for IL-12.
1998).
Both subunits are members of the cytokine receptor
superfamily. IL-12 p40 interacts primarily with IL-
12R(cid:12)1, while IL-12 p35 interacts primarily with
Alternative names
the signal-transducing (cid:12)2 subunit. IL-12 signaling
involvesactivationofthereceptor-associatedtyrosine
kinases JAK2 and TYK2 and downstream tyrosine IL-12R(cid:12)1 was originally termed IL-12R(cid:12) (Presky
phosphorylation of the transcription factors STAT3 et al., 1996).
and STAT4 (the central signal transducer of IL-12).
TheIL-12RisexpressedprimarilyonactivatedTand
NK cells. Expression of the (cid:12)2 subunit determines Structure
TH1 development since the (cid:12)2 component is selec-
tively downregulated on TH2 cells. Inhibiting IL-12
The functional high-affinity IL-12R is a hetero-
responsivenessrepresentsanexperimentaltherapyfor
dimerconsistingofa(cid:12)1anda(cid:12)2chain(Gatelyetal.,
TH1-driven inflammatory and autoimmune diseases.
1998).
Main activities and
BACKGROUND
pathophysiological roles
Discovery
The IL-12R is differentially expressed on T cell sub-
A cDNA encoding a type I transmembrane protein sets. Naı¨ve T cells do not express the IL-12R, while
representing a low-affinity component of the func- antigen stimulation induces expression of both IL-
tional IL-12 receptor was identified on PHA- 12R subunits. Cells developing along the TH1 path-
activated human PBMCs (Chua et al., 1994). way continue to express both receptor components,
Receptors with this type of cytoplasmic region have whereas TH2 cells selectively lose the signal-trans-
been classified as (cid:12)-type cytokine receptors (Stahl ducing component IL-12R(cid:12)2 during differentiation.
and Yancopoulos, 1993). Consequently, the new pro- Consequently, expression levels of the (cid:12)2 subunit
tein was termed IL-12R(cid:12) (Chua et al., 1994). The represent a therapeutic target for the redirection of
corresponding murine cDNA was isolated using ongoingTcellresponses.SeealsoMainactivitiesand
crosshybridization(Chuaetal.,1995).Morerecently, pathophysiological roles in the IL-12 chapter.
1504 Clemens Esche, Michael R. Shurin and Michael T. Lotze
GENE Sequence
Accession numbers See Figure 1. Also see Chua et al. (1994) for human
(cid:12)1,Chuaetal.(1995)formurine(cid:12)1,andPreskyetal.
GenBank: (1996) for (cid:12)2.
Human cDNA: U03187 ((cid:12)1), U64198 ((cid:12)2)
Description of protein
Murine cDNA: U23922 ((cid:12)1), U64199.1 ((cid:12)2)
Chromosome location and linkages The (cid:12)1 subunit is a 662 amino acid type I trans-
membrane protein with an extracellular domain of
516 amino acids and a cytoplasmic domain of 91
Human IL-12R(cid:12)1 localizes to a region in chromo-
amino acids lacking tyrosine residues (Chua et al.,
some 19 at band p13.1, while human IL-12R(cid:12)2
1994). In contrast, the (cid:12)2 subunit, which consists of
localizestochromosome1atbandp31.2(Yamamoto
862 amino acids, has three tyrosine residues in the
et al., 1997).
cytoplasmic domain (Presky et al., 1996).
Relevant homologies and species
PROTEIN
differences
Accession numbers
Both IL-12R subunits are homologous to gp130
GenBank: (a receptor subunit for IL-6), G-CSF, IL-11, onco-
HumanIL-12R:AAA21340.1((cid:12)1),AAB36675.1((cid:12)2) statinM,CNTFandLIFreceptors(Chuaetal.,1994;
MurineIL-12R:AAA87457.1((cid:12)1),AAB36676.1((cid:12)2) Presky et al., 1996; Trinchieri, 1998). Human and
SwissProt: murine IL-12R(cid:12)1 demonstrate a 54% amino acid
Human protein: P42701 ((cid:12)1) homology (Chua et al., 1995). Human and murine
Figure 1 Sequencesfor IL-12R(cid:12)1 and IL-12R(cid:12)2:
Human IL-12Rb 1
1 MEPLVTWVVP LLFLFLLSRQ GAACRTSECC FQDPPYPDAD SGSASGPRDL RCYRISSDRY
61 ECSWQYEGPT AGVSHFLRCC LSSGRCCYFA AGSATRLQFS DQAGVSVLYT VTLWVESWAR
121 NQTEKSPEVT LQLYNSVKYE PPLGDIKVSK LAGQLRMEWE TPDNQVGAEV QFRHRTPSSP
181 WKLGDCGPQD DDTESCLCPL EMNVAQEFQL RRRQLGSQGS SWSKWSSPVC VPPENPPQPQ
241 VRFSVEQLGQ DGRRRLTLKE QPTQLELPEG CQGLAPGTEV TYRLQLHMLS CPCKAKATRT
301 LHLGKMPYLS GAAYNVAVIS SNQFGPGLNQ TWHIPADTHT EPVALNISVG TNGTTMYWPA
361 RAQSMTYCIE WQPVGQDGGL ATCSLTAPQD PDPAGMATYS WSRESGAMGQ EKCYYITIFA
421 SAHPEKLTLW STVLSTYHFG GNASAAGTPH HVSVKNHSLD SVSVDWAPSL LSTCPGVLKE
481 YVVRCRDEDS KQVSEHPVQP TETQVTLSGL RAGVAYTVQV RADTAWLRGV WSQPQRFSIE
541 VQVSDWLIFF ASLGSFLSIL LVGVLGYLGL NRAARHLCPP LPTPCASSAI EFPGGKETWQ
601 WINPVDFQEE ASLQEALVVE MSWDKGERTE PLEKTELPEG APELALDTEL SLEDGDRCKA
661 KM
Human IL-12Rb 2
1 MAHTFRGCSL AFMFIITWLL IKAKIDACKR GDVTVKPSHV ILLGSTVNIT CSLKPRQGCF
61 HYSRRNKLIL YKFDRRINFH HGHSLNSQVT GLPLGTTLFV CKLACINSDE IQICGAEIFV
121 GVAPEQPQNL SCIQKGEQGT VACTWERGRD THLYTEYTLQ LSGPKNLTWQ KQCKDIYCDY
181 LDFGINLTPE SPESNFTAKV TAVNSLGSSS SLPSTFTFLD IVRPLPPWDI RIKFQKASVS
241 RCTLYWRDEG LVLLNRLRYR PSNSRLWNMV NVTKAKGRHD LLDLKPFTEY EFQISSKLHL
301 YKGSWSDWSE SLRAQTPEEE PTGMLDVWYM KRHIDYSRQQ ISLFWKNLSV SEARGKILHY
361 QVTLQELTGG KAMTQNITGH TSWTTVIPRT GNWAVAVSAA NSKGSSLPTR INIMNLCEAG
421 LLAPRQVSAN SEGMDNILVT WQPPRKDPSA VQEYVVEWRE LHPGGDTQVP LNWLRSRPYN
481 VSALISENIK SYICYEIRVY ALSGDQGGCS SILGNSKHKA PLSGPHINAI TEEKGSILIS
541 WNSIPVQEQM GCLLHYRIYW KERDSNSQPQ LCEIPYRVSQ NSHPINSLQP RVTYVLWMTA
601 LTAAGESSHG NEREFCLQGK ANWMAFVAPS ICIAIIMVGI FSTHYFQQKV FVLLAALRPQ
661 WCSREIPDPA NSTCAKKYPI AEEKTQLPLD RLLIDWPTPE DPEPLVISEV LHQVTPVFRH
721 PPCSNWPQRE KGIQGHQASE KDMMHSASSP PPPRALQAES RQLVDLYKVL ESRGSDPKPE
781 NPACPWTVLP AGDLPTHDGY LPSNIDDLPS HEAPLADSLE ELEPQHISLS VFPSSSLHPL
841 TFSCGDKLTL DQLKMRCDSL ML
IL-12 Receptor 1505
IL-12R(cid:12)2 proteins demonstrate a 68% amino acid peripheral blood or tonsillar B lymphoblasts that,
sequence identity (Presky et al., 1996). Although however, failed to bind measurable amounts of IL-12
similar with respect to their molecular properties, (Benjamin et al., 1996; Wu et al., 1996).
significantdifferencesexistbetweenmiceandhumans. TH1 cells express both the (cid:12)1 and (cid:12)2 subunits,
Ba/F3 cells expressing murine IL-12R(cid:12)1 exhibited whereas TH2 cells express only the (cid:12)1 subunit due to
twobindingaffinitiesfor125I-mouseIL-12:50pMand selective downregulation of (cid:12)2 (Rogge et al., 1997;
470pM (Chua et al., 1995), while Ba/F3 cells trans- Szabo et al., 1997). Consequently, only TH1 cells are
fected with human IL-12R(cid:12)1 bound 125I-human IL- capable of signaling in response to IL-12. Murine
12onlywithverylowaffinity(>50nM)(Preskyetal., B10.D2TcellsexpressIL-12R(cid:12)2atsufficientlevelsto
1996). These differences should be considered when allowfunctionalresponsestoIL-12,whereasBalb/cT
evaluating potential therapeutic IL-12 antagonists cells express lowlevels of (cid:12)2 and demonstrate limited
directed against IL-12R in murine models of human functional IL-12-induced STAT4 phosphorylation
disease.Furthermore,expressionofIL-12R(cid:12)2mRNA (Guler et al., 1997).
is regulated differentially in mice and humans. In
mice, IFN(cid:13) treatment of early developing TH2 cells
maintains IL-12R(cid:12)2 expression (Szabo et al., 1997). Regulation of receptor expression
In humans, IFN(cid:11) induces expression of IL-12R(cid:12)2
during in vitro T cell differentiation (Rogge et al., IL-4 rapidly extinguishes IL-12R (cid:12)2 chains in vitro
1997). (Szabo et al., 1997; Wu et al., 1997a) and in vivo
(Himmelrich et al., 1998), while IFN(cid:13) maintains the
ability to signal through IL-12R(cid:12)2 both in vitro
Affinity for ligand(s)
(Szabo et al., 1997) and in vivo (Himmelrich et al.,
1998). Thus, IFN(cid:13) and IL-4 promote the develop-
Analysis of steady-state binding data of IL-12 by ment of TH1 and TH2 responses by differential
Scatchard analysis identified a single binding site on regulationofIL-12receptorexpression(Gollobetal.,
PHA-activated human lymphoblasts with an equilib- 1997). TGF(cid:12) and IL-10 prevent TH1 responses by
rium dissociation constant of 100–600pmol/L and nearly completely suppressing expression of high-
1000–9000 sites per cell (Chizzonite et al., 1992). affinityIL-12-bindingsites,whereasexpressionofIL-
More recently, three classes of IL-12-binding sites 12R(cid:12)1 is only partially inhibited (Wu et al., 1997a).
were identified on PHA-activated human T lympho- Cholera toxin inhibits the expression of both (cid:12)1 and
blasts: high-affinity (K (cid:136)5–20pM) (100–1000 sites/ (cid:12)2 chains (Braun et al., 1999). T cells from patients
d
cell), intermediate-affinity (K (cid:136)50–200pM) (200– with Sezary syndrome express little or no message for
d
1000sites/cell),andlow-affinity(K (cid:136)2–6nM)(1000– the IL-12R(cid:12)2 subunit and exhibit highly reduced
d
5000 sites/cell) (Chua et al., 1994; Stern et al., 1997). levels of STAT4 (Showe et al., 1999). Prostaglandin
Both IL-12R(cid:12)1 and IL-12R(cid:12)2 bind IL-12 with only E (PGE ) and dexamethasone inhibit IL-12R(cid:12)1
2 2
low affinity when transfected into COS-7 cells. expressionandmRNAforIL-12R(cid:12)2(Wuetal.,1998).
However, coexpression of both human subunits In contrast, IL-2, IL-7, IL-15, phytohemagglutinin
results in high- (K (cid:136)55pM) and low-affinity IL-12- (PHA) and anti-CD3 monoclonal antibodies induce
d
binding sites (K (cid:136)8nM) and a receptor complex IL-12R(cid:12)1 expression (Wu et al., 1997a). The natural
d
capableofsignaling(Preskyetal.,1996).Dissociation killer T (NKT) cell ligand (cid:11)-galactosylceramide
constants on concanavalin (Con A)-stimulated ((cid:11)-GalCer) induces mRNA for both IL-12R(cid:12)1 and
murine splenocytes were determined to be 40pM IL-12R(cid:12)2 (Kitamura et al., 1999). Upregulation of
(100–500 sites/cell), 200pM (600–800 sites/cell) and the receptor correlates with the ability of the cells to
7nM (1000–2000 sites/cell) (Stern et al., 1997). proliferate in response to IL-12 (Chizzonite et al.,
1992; Desai et al., 1992).
Cell types and tissues expressing
the receptor SIGNAL TRANSDUCTION
Associated or intrinsic kinases
PresencewasdetectedmostlyonactivatedTcellsand
NKcells (Desaietal.,1992).Dendriticcells expressa
singleclassofhigh-affinityIL-12R(Grohmannet al., IL-12 receptor stimulation activates the receptor-
1998).In addition,IL-12R(cid:12)1 was detected on human associated tyrosine kinases JAK2 and TYK2 (Bacon
B cell lines and was upregulated on activated human et al., 1995a).In addition, an isoform of MAP kinase
1506 Clemens Esche, Michael R. Shurin and Michael T. Lotze
is phosphorylated (Pignata et al., 1994). IL-12 also Genes induced
inducestyrosinephosphorylationofthesrcfamilylck
tyrosine kinase (Pignata et al., 1995).
IL-12 induces upregulation of IFN(cid:13) (with costimulus
ofIL-18),theIL-18R(Xuetal.,1998),theIL-12R(cid:12)2,
IRF-1 (Coccia et al., 1999), ERM (Ouyang et al.,
Cytoplasmic signaling cascades
1999) and other, yet to be identified genes.
IL-12bindingtoitsreceptoronTandNKcellsinduces
simultaneous activation of two members of the Janus Promoter regions involved
kinase (JAK) family of protein tyrosine kinases,
JAK2 and TYK2 (Bacon et al., 1995a). TYK2 inter-
Early reports suggested that IL-12 alone does not
acts with the (cid:12)1 subunit of the IL-12 receptor and
activate IFN(cid:13) promoter activity (Jacobson et al.,
JAK2interactswiththe(cid:12)2subunit(Zouetal.,1997).
1995). However, c-Jun represents at least one
Both JAK2 and TYK2 also transduce signals via
transcription factor induced by IL-12 that binds to
other cytokine receptors including type 1 (Velazquez
the IFN(cid:13) promoter and can stimulate transcription
etal.,1992)andtype2IFN(Watlingetal.,1993),IL-
(Zhang et al., 1999). In addition, IL-12 strongly
3 (Silvennoinen et al., 1993), IL-6 (Stahl et al., 1994),
induces IFN(cid:13) promoter activity in the presence of
and GM-CSF (Quelle et al., 1994). NOS2-derived
costimulatory signals provided by soluble antibodies
nitric oxide is a prerequisite for IL-12-induced acti-
to CD3 and CD28 (Barbulescu et al., 1998). Both
vation of TYK2 in NK cells (expressing NOS2) but
STAT4 and AP-1 are required for IFN(cid:13) promoter
notinTcells(lackingNOS2)(Diefenbachetal.,1999).
activation(Barbulescuetal.,1998).ActivatedSTAT4
JAK kinases phosphorylate the IL-12 receptor on
binds to the GAS element in the IRF-1 promoter
tyrosines located in the intracellular domain. The
(Cocciaetal.,1999).Theprecisemechanismbywhich
phosphorylated regions are binding sites for tran-
STAT proteins mediate transcriptional activation
scription factors termed signal transducers and acti-
remain to be elucidated (Hoey and Grusby, 1999).
vators of transcription (STAT). IL-12 binding to its
receptor results in activation of three members of
the STAT family. STAT1 can dimerize with either
BIOLOGICAL CONSEQUENCES
STAT3 or STAT4 and STAT4 can dimerize with
STAT3 (Jacobson et al., 1995; Yu et al., 1996). OF ACTIVATING OR
Only STAT4, but neither STAT1 nor STAT3 is INHIBITING RECEPTOR AND
activated directly throughthe IL-12 receptor (Naeger
PATHOPHYSIOLOGY
et al., 1999). Only IL-12 and IFN(cid:11) induce tyrosine
phosphorylationandDNAbindingofSTAT4(Bacon
Unique biological effects of
etal.,1995b;Choetal.,1996).Thissignalingpathway
isthereforerelativelyspecifictoIL-12.Deletionofthe activating the receptors
STAT4 gene in knockout mice results in defective
responses specific to IL-12 (Thierfelder et al., 1996;
Antibodies that activate the receptor have not been
Kaplan et al., 1996). Tyrosine phosphorylation of
identified.
STAT proteins induces their dimerization and subse-
quenttranslocationtothenucleuswheretheybindto
related DNA sequences and regulate transcription Phenotypes of receptor knockouts
(Darnell et al., 1994). Signaling induced by IL-12
and receptor overexpression mice
varies with the particular cell evaluated.
IL-12R(cid:12)1-deficient (IL-12R(cid:12)1(cid:255)/(cid:255)) mice are grossly
DOWNSTREAM GENE indistinguishable from their control littermates (Wu
etal.,1997b).However,splenocytesfromIL-12R(cid:255)/(cid:255)
ACTIVATION
are deficient in all IL-12-induced biologic activities
including proliferation, IFN(cid:13) secretion, TH1 devel-
Transcription factors activated
opment and enhancement of NK lytic activity (Wu
etal.,1997b).Inaddition,IL-12R(cid:12)1(cid:255)/(cid:255)miceexhibit
STAT1, STAT3, STAT4 (Trinchieri, 1998), NF(cid:20)B a severe defect in their ability to generate IFN(cid:13)-
and c-Jun (Zhang et al., 1999) are all activated by producingTH1cells,whereasgenerationofTH2cells
IL-12R. is moderately enhanced (Wu et al., 1997b).
IL-12 Receptor 1507
Human abnormalities Chizzonite,R.,Truitt,T.,Desai,B.B.,Nunes,P.,Podlaski,F.J.,
Stern, A. S., and Gately, M. K. (1992). IL-12 receptor. I.
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12R(cid:12)1subunithavebeenidentifiedinsevenunrelated Cho, S. S., Bacon, C. M., Sudarshan, C., Rees, R. C.,
individuals with idiopathic mycobacterial and Finbloom, D., Pine, R., and O’Shea, J. J. (1996). Activation
of STAT4 by IL-12 and IFN-alpha: evidence for the involve-
Salmonella infections (Altare et al., 1998; de Jong
ment of ligand-induced tyrosine and serine phosphorylation.
et al., 1998). Their cells were deficient in IL-12R sig-
J.Immunol.157,4781–4789.
naling and IFN(cid:13) production and their remaining Chua,A.O.,Chizzonite,R.,Desai,B.B.,Truitt,T.P.,Nunes,P.,
T cell responses were independent of endogenous Minetti, L. J., Warrier, R. R., Presky, D. H., Levine, J. F.,
IL-12. Thus, the lack of IL-12R(cid:12)1 expression results Gately, M. K., and Gubler, U. (1994). Expression cloning
of a human IL-12 receptor component. A new member of the
in a human immunodeficiency and demonstrates the
cytokine receptorsuperfamily withstronghomologytogp130.
essential role of IL-12 in resistance to infections due
J.Immunol.153,128–136.
to intracellular bacteria. Chua, A. O., Wilkinson, V. L., Presky, D. H., and Gubler, U.
(1995). Cloning and characterization of a mouse IL-12 recep-
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and Rogge, L. (1999). Interleukin-12 induces expression of
interferonregulatoryfactor-1viasignaltransducerandactiva-
Effects of inhibitors (antibodies)
tor of transcription-4 in human T helper type 1 cells. J. Biol.
Chem.274,6698–6703.
to receptors
DarnellJr.,J.E.,Kerr,I.M.,andStark,G.R.(1994).Jak-STAT
pathwaysandtranscriptionalactivationinresponsetoIFNsand
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deJong,R.,Altare,F.,Haagen, I.A.,Elferink, D.G.,Boer,T.,
IL-12-induced proliferation of activated T cells, IL-
van Breda Vriesman, P. J., Kabel, P. J., Draaisma, J. M.,
12-induced secretion of IFN(cid:13) by resting PBMCs,
van Dissel, J. T., Kroon, F. P., Casanova, J. L., and
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Desai, B. B., Quinn, P. M., Wolitzky, A. G., Mongini, P. K.,
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IL-12 Receptor 1509
LICENSED PRODUCTS ACKNOWLEDGEMENTS
IL-12R has not been licensed. This work has been supported in part by the 1999
R&D Systems (www.rndsystems.com), Sigma Advanced Polymer Systems Research Fellowship of
(www.sigma-aldrich.com). the Dermatology Foundation to CE, NIH Grant CA
Antibodies: 80126 to MRS, and NIH Grants CA 68067 and CA
Flow cytometry: PharMingen 73743 to MTL. We apologize to all colleagues whose
(www.pharmingen.com) contributionshavenotbeendirectlyreferencedinthis
chapter.