IL-1 Receptor Type I

14 Pages·0.141 MB·English

by  Dinarello Ch.A.

IL-1 Receptor Type I
Charles A. Dinarello*
Department of Infectious Diseases, University of Colorado Health Sciences Center,
4200 East Ninth Avenue, B168, Denver, CO 80262, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.15001.
SUMMARY in retrospect, was the IL-1RI (Mosley et al., 1987;
Birdetal.,1987;Chinetal.,1988;Qwarnstrometal.,
TheIL-1receptortypeIistheligand-bindingchainof 1988; Scapigliati et al., 1989; Savage et al., 1989).
the IL-1 heterodimer complex. It is a three-domain
Ig-like extracellular receptor with a cytoplasmic
Structure
domain containing the Toll protein-like sequences.
The IL-1 R type I does not function without the
second chain of the dimer, namely the IL-1R acces- TheextracellulardomainsoftheIL-1RIaretypicalof
sory protein. Although the IL-1R accessory protein an Ig-like receptor of the fibroblast growth factor
chain does contain similar extracellular domains as family. The 80kDa glycoprotein has three Ig-like
thetypeI,itdoesnotbindIL-1insolution.However, domains in the extracellular segment, a transmem-
the IL-1R accessory protein, together with the IL- brane domain, and a cytoplasmic domain containing
1RI, form a complex with the IL-1 ligand (IL-1(cid:11) or the Toll-like protein of Drosophila (Gay and Keith,
IL-1(cid:12)) with a high affinity. 1991).
Soluble forms of the IL-1RI, produced by pro-
teolytic cleavage, are found in the circulation of
healthy humans and in elevated levels during disease.
Main activities and
The soluble IL-1RI has an unusually high binding
constant to the IL-1Ra and hence with preferentially pathophysiological roles
bind this antagonist member of the IL-1 family.
AlthoughinanimalsadministrationofsolubleIL-1RI
When IL-1 binds to the cell membrane of IL-1RI, it
has reduced the severity of disease, in humans with
recruits the IL-1R accessory protein (IL-1R AcP).
rheumatoid arthritis this method of neutralizing IL-1
The heterodimer of the IL-1RI and the IL-1R AcP
has not been successful because it binds IL-1Ra
initiate signal transduction.. A soluble form of this
before it binds IL-1(cid:11) or IL-1(cid:12).
receptor has been described that acts to reduce the
biological effects of IL-1 (Dower et al., 1989).
BACKGROUND
Discovery GENE
Accession numbers
The molecular cloning of the IL-1 receptor type I
(IL-1RI) was first made in the mouse (Sims et al.,
1988). Earlier, several groups had described an ThegenefortheIL-1RIhasbeenreported(Simsetal.,
80kDa glycoprotein on T cells and fibroblasts. This, 1995).
1588 Charles A. Dinarello
Sequence similarsignals(Guidaetal.,1992;Heguyetal.,1992).
Because of the finding of the Toll protein in the
cytoplasmic domain of other receptors (IL-18, for
ThesequenceofthehumanIL-1RIgenecanbefound
example), IL-1RI belongs to an entire family of
in Sims et al., (1995).
receptors characterized by their common cytoplasmic
Tolldomains.Thisfamilyiscalled Toll-likereceptors
(TLR) and is discussed in detail in the chapter on the
PROTEIN
IL-1 receptors.
Description of protein
Relevant homologies and species
The extracellular domains of the IL-1RI form a
differences
typical Ig-like receptor. It is in the same family as the
fibroblast growth factor family. The glycoprotein has
There is considerable homology between the IL-1RI
three Ig-like domains in the extracellular segment, a
and IL-1R AcP in the extracellular and cytoplasmic
transmembrane domain and a cytoplasmic domain
domains but only in the extracellular domains of
(Sims et al., 1988). Glycosylation of IL-1RI appears
IL-1RII in all species. The extracellular domains of
to be necessary for optimal activity (Mancilla et al.,
theIL-1RIsharehomologiestoIL-1R-relatedprotein
1992). In fact, IL-1RI is heavily glycosylated and
(Parnetetal.,1996)andtheST2receptor(Gayleetal.,
blocking the glycosylation sites reduces the binding
1996).
of IL-1. Surface expression of this receptor is likely
on most IL-1-responsive cells as biological activity of
IL-1isabetterassessmentofreceptorexpressionthan
Affinity for ligand(s)
ligand binding to cell surfaces (Rosoff et al., 1988).
Failuretoshowspecific andsaturableIL-1bindingis
often due to the low numbers of surface IL-1RI on Although the type I receptor binds IL-1(cid:11) or IL-1(cid:12)
primary cells. In cell lines, the number of IL-1RI can and transmits a signal upon complex formation with
reach 5000 per cell, but primary cells usually express the IL-1R AcP, of the three members of the IL-1
less than 200 receptors per cell. In some primary cells family, IL-1(cid:12) has the lowest affinity for the cell-
there are less than 50 per cell (Shirakawa et al., 1987) bound form of IL-1RI (500pM–1nM). The greatest
and IL-1 signal transduction has been observed in binding affinity of the three IL-1 ligands for the IL-
cells expressing less than 10 type I receptors per cell 1RIisthatofIL-1Ra.Infact,theoff-rateisslowand
(Stylianouetal.,1992).ThelownumberofIL-1RIon binding of IL-1Ra to IL-1RI is nearly irreversible.
cells and the discrepancy between binding affinities After IL-1Ra, IL-1(cid:11) binds to IL-1RI with affinities
and biological activities can be explain by the ranging from 100 to 300pM. By comparison, IL-1(cid:12)
increased binding affinity of IL-1 in the complex binds more avidly to the nonsignal transducing type
with the IL-1R AcP (Greenfeder et al., 1995). II receptor (100pM). IL-1(cid:12) binding to the soluble
IL-1RI has a single transmembrane segment and a form of the IL-1RI is lower compared to the cell-
cytoplasmic domain. Using specific neutralizing anti- bound receptor.
bodies, IL-1RI but not IL-1RII is the primary signal Differencesexistinthebindingaffinity,association
transducing receptor. Antisense oligonucleotides and dissociation rates of the mature forms of each
directed against IL-1RI block IL-1 activities in vitro member of the IL-1 family to cell-bound IL-1RI and
and in vivo (Burch and Mahan, 1991). The cytoplas- soluble IL-1RI receptors. In some cells, there is a
mic domain of IL-1RI has no apparent intrinsic discrepancy between the dissociation constant of
tyrosinekinaseactivitybutwhenIL-1bindstoonlya eitherformofIL-1(usually200–300pM)andconcen-
few receptors, the remaining unoccupied receptors trations of IL-1 which can elicit a biological response
appear to undergo phosphorylation (Gallis et al., (10–100fM). In cells expressing large amounts of IL-
1989), probably by a member of the MAP kinase 1RAcP,thehigh-affinitybindingoftheIL-1R/IL-1R
family. Interestingly, the cytosolic domain of IL-1RI AcPcomplexmayexplainwhytwoclassesofbinding
has a 45% amino acid homology with the cytosolic have been observed. Human recombinant 17kDa IL-
domain of the Drosophila Toll gene (Gay and Keith, 1(cid:11) binds to cell surface and soluble type I receptors
1991). Toll is a transmembrane protein acting like a withapproximatelythesameaffinity(100–300pM).If
receptor. Gene organization and amino acid homol- the binding of IL-1Ra is examined, the affinity is
ogy suggests that the IL-1RI and the cytosolic Toll even higher than that of IL-1(cid:11). IL-1Ra avidly binds
are derived from a common ancestor and trigger to the surface type I receptor (50–100pM). Although
IL-1 Receptor Type I 1589
IL-1Rabindslesssothesolubleformofthisreceptor, et al., 1994). In the case of TH2 lymphocytes, IL-1
it is, nevertheless, a high-affinity binding. downregulates IL-1RI surface expression and this is
associated with a decrease in mRNA half-life (Ye
Cell types and tissues expressing et al., 1992). Therefore, despite the housekeeping
nature of its promoters, IL-1RI is regulated in the
the receptor
context of inflammation and immune responses.
Usinginsituhybridization,IL-1RIgeneexpression
IL-1RI is found predominantly on endothelial cells,
can be detected in the endocrine pancreas, cardiac
smooth muscle cells, epithelial cells, hepatocytes,
endothelium, epidermis, hair follicles, uterine serosa,
fibroblasts, keratinocytes, epidermal dendritic cells,
developingoocytesandgranulosacellsfromruptured
and T lymphocytes.
ovarianfolliclesofhealthymice(Deyerleetal.,1992).
In contrast, the spleen and thymus are largely nega-
tive. IL-1RI has also been localized to specific hippo-
Regulation of receptor expression
campalareasofthenormalmousebrain,adrenaland
testis (Cunningham et al., 1991). There is an uneven
The genomic organization of the human type I distributionwithlocalizationinthehippocampus,the
receptor reveals three distinct transcription initiation anterior lobe of the pituitary gland, and the dentate
sites contained in three separate segments of the first gyrus (Deyerle et al., 1992). The importance of con-
exonwhichisdistributedover29kbofthegene(Sims stitutive gene expression for IL-1RI in ontogeny and
et al., 1995).Each part ofthisfirst exon is thoughtto homeostasisisunclearsincemicedeficientinthisgene
possess a separate promoter which functions inde- exhibitagrosslynormalphenotype(Labowetal.,1997).
pendentlyindifferentcells(Simsetal.,1995;Yeetal.,
1996). Despite evidence that type I receptor gene
Release of soluble receptors
expression can be upregulated in vitro (Koch et al.,
1992; Ye et al., 1992), the most proximal (50)
promoter region lacks a TATA or CAAT box (Ye In contrast to the IL-1RII in which LPS induces a
et al., 1996). In fact, this promoter region for the rapid shedding of the extracellular domain, LPS
human IL-1RI shares striking similarity to those of induced IL-1RI and also surface IL-1R AcP expres-
housekeeping genes rather than highly regulated sion (Penton-Rol et al., 1999). In addition to the
genes. The transcription initiation start site contains major 5kb IL-1RI mRNA the 2.4kb IL-1RI tran-
nearly the same motif as that for the TdT gene (Ye scripts were observed. The 2.4kb inducible band
et al., 1993). There is a G(cid:135)C-rich segment (75%) includes incompletely spliced, polyadenylated tran-
following the transcription initiation site of exon I scripts which may encode for truncated receptors.
which accounts for considerable secondary RNA Thus, LPS has divergent effects on IL-1 receptors by
structure. Low numbers of surface IL-1RI may, in increasing soluble IL-1RII butstimulating expression
fact, be due to multiple secondary RNA structures of IL-1RI and IL-1R AcP.
which reduce optimal translation of the mRNA (Ye Soluble receptors for IL-1RI have been found in a
et al., 1996). variety of disease states. Soluble type II IL-1R are
Surface expression of IL-1RI clearly impacts upon found in the circulation and urine of healthy subjects
thebiologicalresponsetoIL-1.SimilartoIL-1(cid:12),cells and in inflammatory synovial and other pathologic
can express high steady-state levels of mRNA for IL- body fluids. In healthy humans, the circulating levels
1RIbutlowlevelsoftheprotein.Thismaybeduethe of IL-1sRI and IL-1sRII are 50–100pM. The rank of
amount of secondary structure in each of the affinitiesfortheIL-1RIsolublereceptorsareremark-
polyadenylated RNA species. Studies on IL-1R sur- ably different for each of the three IL-1 molecules.
face expression have mostly used binding of labeled TherankforthethreeIL-1ligandsbindingtosoluble
ligands rather than assessment of surface receptor IL-1RI is IL-1Ra>IL-1(cid:11)>IL-1(cid:12). Elevated levels of
density using specific antibodies. Nevertheless, phor- solubleIL-1RIarefoundinthecirculationofpatients
bol esters, PGE , dexamethasone, epidermal growth withsepsis,inthesynovialfluidofpatientswithactive
2
factor, IL-2, and IL-4 increase surface expression of rheumatoid arthritis (Arend et al., 1994) and in pa-
IL-1RI. In cells which synthesize PGE , IL-1 upregu- tients with hairy cell leukemia (Barak et al., 1996). In
2
latesitsownreceptorviaPGE ;however,whenPGE patientsundergoingaortaresection,crossclampingof
2 2
synthesis is inhibited, IL-1 downregulates IL-1RI in the aorta results in significant ischemia and a dra-
the same cells (Takii et al., 1992, 1994; Pronost et al., matic release of soluble IL-1R I (Pruitt et al., 1996).
1993). TGF(cid:12) and IL-1 downregulate surface expres- Similar to IL-1RI and IL-1RII, a soluble form of
sion ofIL-1RI onT cells (Duboiset al., 1990; Silvera the IL-1R AcP exists but this form appears to result
1590 Charles A. Dinarello
fromanRNAsplicedonor/acceptorsiteresultingina amino acids (Arg431, Lys515, and Arg518), also
truncated protein ending before the transmembrane found in the Toll protein, are essential for IL-1-
region. Unlike the soluble forms of the IL-1RI and inducedIL-2production(Heguyetal.,1992).However,
IL-1RII, the soluble IL-1R AcP is not formed by deletion of a segment containing these amino acids
proteolytic cleavage of the full-length accessory pro- did not affect IL-1-induced IL-8 (Kuno et al., 1993).
tein. It is unclear how soluble IL-1R AcP mRNA is TherearealsotwocytoplasmicdomainsintheIL-1RI
expressed compared to the cell-bound protein. which share homology with the IL-6-signaling gp130
Furthermore, since the IL-1R AcP does not bind receptor. When these regions are deleted, there is a
IL-1 itself (Greenfeder et al., 1995), the effect of the loss of IL-1-induced IL-8 production (Kuno et al.,
soluble IL-1R AcP on the binding of IL-1 remains 1993).
unclear. The C-terminal 30 amino acids of the IL-1RI can
be deleted without affecting biological activity
(Croston et al., 1995). Two independent studies have
focusedontheareabetweenaminoacids513and529.
SIGNAL TRANSDUCTION
Amino acids 508–521 contain sites required for the
activation of NF(cid:20)B. In one study, deletion of this
Associated or intrinsic kinases
segment abolished IL-1-induced IL-8 expression and
in another study, specific mutations of amino acids
Hopp reported a detailed sequence and structural 513 and 520 to alanine prevented IL-1-driven E-
comparison of the cytosolic segment of IL-1RI with selectin promoter activity. This area is also present in
the ras-family of GTPases (Hopp, 1995). In this the Toll protein domain associated with NF(cid:20)B
analysis, the known amino acids residues for GTP translocation and previously shown to be part of
binding and hydrolysis by the GTPase family were the IL-1 signaling mechanism. This area (513–520) is
found to align with residues in the cytoplasmic also responsible for activating a kinase which asso-
domainoftheIL-1RI.Inaddition,Rac,amemberof ciates with the receptor. Termed IL-1RI-associated
the Rho family of GTPases, was also present in the kinase, this kinase phosphorylates a 100kDa sub-
binding and hydrolytic domains of the IL-1RI strate.Othershavereportedaserine/threoninekinase
cytosolic domains. These observations are consistent that coprecipitates with the IL-1RI (Martin et al.,
with the observations that GTP analogs undergo a 1994). Amino acid sequence comparisons of the
rapid hydrolysis when membrane preparations of IL- cytosolic domain of the IL-1RI have revealed simi-
1RIareincubatedwithIL-1.Aminoacidsequencesin larities with a protein kinase C (PKC) acceptor site.
thecytosolicdomainoftheIL-1RAcPalsoalignwith Because PKC activators usually do not mimic IL-1-
the same binding and hydrolytic regions of the inducedresponses,thesignificanceofthisobservation
GTPases (T. P. Hopp, personal communication). A is unclear.
protein similar to G protein-activating protein has
been identified which associates with the cytosolic
Recruitment of MyD88 and IL-1
domainoftheIL-1RI(MichumandSims,1995).This
Receptor Activating Kinase
finding is consistent with the hypothesis that an early
event in IL-1R signaling involves dimerization of the An event that may be linked to the binding of G
two cytosolic domains, activation of putative GTP- proteins to the IL-1 receptor complex is the
bindingsitesonthecytosolicdomains,bindingofaG recruitment of the cytosolic protein called MyD88.
protein, hydrolysis of GTP and activation of a phos- This small protein has many of the characteristics of
pholipase. It then follows that hydrolysis of phos- cytoplasmic domains of receptors but lacks any
pholipids generates diacylglycerol or phosphatidic knownextracellularortransmembranestructure.Itis
acids. unclear exactly how this protein functions, since it
doesnothaveanyknownkinaseactivity.However,it
mayassistinthebindingofIRAKtothecomplexand
Characteristics of the Cytoplasmic
hence has been said to function as an adapter mole-
Domain of the IL-1RI
cule. The binding of IRAK to the IL-1R complex
The cytoplasmic domain of the IL-1RI does not appearstobeacriticalstepintheactivationofNF(cid:20)B
contain a consensus sequence for intrinsic tyrosine (Croston et al., 1995). The IL-1R AcP is essential for
phosphorylation but deletion mutants of the receptor therecruitmentandactivationofIRAK(Huangetal.,
reveal specific functions of some domains. There are 1997;Wescheetal.,1997).Infact,deletionofspecific
four nuclear localization sequences which share amino acids in the IL-1R AcP cytoplasmic domain
homology with the glucocorticoid receptor. Three results in loss of IRAK association (Wesche et al.,
IL-1 Receptor Type I 1591
1997). In addition, the intracellular adapter molecule IRAK also associates with the IL-18R complex
termed MyD88 appears to dock to the complex, (Robinson et al., 1997;Kojima et al., 1998).This was
allowing IRAK to become phosphorylated (Croston demonstrated using IL-12-stimulatedT cells followed
et al., 1995; Cao, 1998). IRAK then dissociates from by immunoprecipitation with anti-IL-18R or anti-
theIL-1RcomplexandassociateswithTNFreceptor- IRAK (Kojima et al., 1998). Furthermore, IL-18-
associated factor 6 (TRAF6) (Cao et al., 1996). triggered cells also recruited TRAF6 (Kojima et al.,
TRAF6 then phosphorylates NIK (Malinin et al., 1998).LikeIL-1signaling,MyD88hasaroleinIL-18
1997) and NIK phosphorylates the inhibitory (cid:20)B signaling. MyD88-deficient mice do not produce
kinases (IKK-1 and IKK-2) (DiDonato et al., 1997). acute phase proteins and have diminished cytokine
Once phosphorylated, I(cid:20)B is rapidly degraded by a responses. Recently, TH1-developing cells from
ubiquitin pathway, liberating NF(cid:20)B which translo- MyD88-deficient mice were unresponsive to IL-18-
cates to the nucleus for gene transcription. induced activation of NF(cid:20)B and c-Jun N-terminal
In mice deficient in TRAF6, there is no IL-1 kinase (JNK) (Adachi et al., 1998). Thus, MyD88 is
signaling in thymocytes and the phenotype exhibits an essential component in the signaling cascade that
severe osteopetrosis and defective formation of follows IL-1 receptor as well as IL-18 receptor
osteoclasts (Lomaga et al., 1999). binding. It appears that the cascade of sequential
recruitment of MyD88, IRAK, and TRAF6 followed
by the activation of NIK and degradation of I(cid:20)BK
IL-1 and IL-18 Signaling are Similar
and release of NF(cid:20)B are nearly identical for IL-1 as
A review of the biology of IL-18 has been published well as forIL-18. Indeed, in cells transfected with IL-
(Dinarello, 1999). There are both high (0.4nM) and 18R(cid:11) (IL-1Rrp) and then stimulated with IL-18,
low(40nM) affinitybindingsites for IL-18 in murine translocation of NF(cid:20)B takes is observed using
primaryTcells(Yoshimotoetal.,1998).Clearlythere electromobility shift assay (Torigoe et al., 1997). In
aretwochainstotheIL-18receptorcomplex.Similar U1 macrophages, which already express the gene for
to the nomenclature for other heterodimeric recep- IL-1Rrp, there is translocation of NF(cid:20)B and stimu-
tors, there is an (cid:11) chain which functions as a ligand- lation of HIV-1 production (Shapiro et al., 1998a).
binding chain and a (cid:12) chain which is the signaling
chain. For IL-18, the ligand-binding chain was
Cytoplasmic signaling cascades
isolated and found to be a member of the IL-1R
family. Hence the IL-18R(cid:11) had been previous cloned
and called the IL-1R-related protein IL-1Rrp (Parnet SignaltransductionofIL-1dependsontheformation
et al., 1996). This receptor remained an orphan of a heterodimer between IL-1RI and IL-1R AcP
receptor until the work by Torigoe et al., (1997). The (Greenfeder et al., 1995). This interaction recruits
binding of a second chain would explain the higher MyD88, a cytoplasmic adapter molecule. This is fol-
affinity. This ‘other’ receptor chain has been iden- lowed by recruitment of the IL-1R-activating kinase
tified as the ‘accessory protein-like’ (AcPL) receptor (IRAK)(Crostonetal.,1995;Caoetal.,1996;Huang
(Bornetal.,1998),andisrelatedtotheIL-1accessory etal.,1997).AntibodiestoIL-1RIblockIL-1activity.
protein identified by Greenfeder et al. (1995). Similar Although IL-1R AcP does not bind IL-1, antibodies
to the IL-1 accessory protein, the IL-18 AcPL does to IL-1R AcP also prevent IL-1 activity (Yoon and
notbindtoitsligand butratherbindstothe complex Dinarello,1998).Boththeextracellulardomainofthe
formedbyIL-18withtheIL-18R(cid:11)chain(Bornetal., IL-1R AcP and its cytoplasmic segment share homo-
1998). This heterodimeric is probably the high- logy with the IL-1RI. There is a perfectly conserved
affinity complex. protein kinase C acceptor site in both cytoplasmic
Therefore, it is likely that the IL-18 receptor domains, although agents activating protein kinase C
complexiscomprisedofaligand-bindingchainofIL- do not mimic IL-1 signal transduction. Limited
1Rrp(IL-18R(cid:11))withthesecondchainbeingthenon- sequence homologyofthegp130cytoplasmicdomain
IL-18 binding AcPL (IL-18R(cid:11)) (Born et al., 1998). with those of IL-1RI (Kuno and Matsushima, 1994)
AnIL-18-bindingprotein(IL-18BP)hasbeenpurified andIL-1RAcPsuggestthatcomplexformationofthe
from human urine and cloned (Novick et al., 1999). IL-1R/IL-1/IL-1R AcP transduces a signal similar to
But a transmembrane form of the IL-18BP has not that observed with ligands which cause the dimeriza-
been isolated to date despite murine cDNA cloning tion of gp130. In fact, deletion of the gp130-shared
and human genomic analyses (Novick et al., 1999). sequences from the IL-1RI cytoplasmic domain
Thus, the IL-18BP is a third gene product and results in a reduced response to IL-1 (Kuno and
appearstobethe‘decoy’receptorofIL-18,similarto Matsushima, 1994). IL-1 shares some prominent
theIL-1RtypeIIwhichisthedecoyreceptorforIL-1. biologicalpropertieswithgp130ligands;forexample,
1592 Charles A. Dinarello
fever, hematopoietic stem cell activation, and the complex. A rather extensive ‘amplification’ step(s)
stimulationofthehypothalamic-pituitary-adrenalaxis takes place following the initial postreceptor binding
arecommontoIL-1andIL-6.Otherbiologicalactiv- event. The most likely mechanism for signal ampli-
ities of IL-1 and IL-6 are distinctly antagonistic. fication is multiple and sequential phosphorylations
High levels of IL-1R AcP are expressed in mouse (or dephosphorylations) of kinases which result in
and human brain tissue. The discovery and function nuclear translocation of transcription factors and
of the IL-1R AcP has placed IL-1 receptor biology activation of proteins participating in translation of
and signaling mechanisms into the same arena as mRNA. IL-1RI is phosphorylated following IL-1
other cytokines and growth factors. The IL-1R AcP binding. It is unknown whether the IL-1R AcP is
also explains previous studies describing low- and phosphorylated during receptor complex formation.
high-binding affinities of IL-1 to various cells. Like Inprimarycells,thenumberofIL-1RtypeIreceptors
other models of two-chain receptors, IL-1 binds first is very low (<100 per cell) and a biological response
totheIL-1RIwithalowaffinity.Althoughthereisno occurs when only as few as 2–3% of them are
directevidence, astructuralchangemaytakeplacein occupied(Gallisetal.,1989;Yeetal.,1992).InIL-1-
IL-1 allowing for docking of IL-1R AcP to the IL- responsivecells,oneassumesthatthereisconstitutive
1RI/IL-1 complex. Once IL-1RI/IL-1 binds to IL-1R expression of the IL-1R AcP.
AcP, a high-affinity binding is observed. Antibodies With few exceptions, there is general agreement
tothetypeIreceptorandtotheIL-1RAcPblockIL- that IL-1 does not stimulate hydrolysis of phospha-
1 binding and activity. Therefore, IL-1 may bind to tidylinositol nor an increase in intracellular calcium.
the type I receptor with a low affinity, causing a Withoutaclearincreaseinintracellularcalcium,early
structural change in the ligand followed by recogni- postreceptor binding events nevertheless include
tion by the IL-1R AcP. hydrolysis of a GTP with no associated increase in
Within a few minutes following binding to cells, adenyl cyclase, activation of adenyl cyclase (Minzel,
IL-1 induces several biochemical events (reviewed by 1990; Munoz et al., 1990), hydrolysis of phospholi-
Rossi, 1993; Kuno and Matsushima, 1994; Brooks pids (Rosoff et al., 1988; Kester et al., 1989), release
and Mizel, 1994; Martin and Falk, 1997). It remains of ceramide (Mathias et al., 1993), and release of
unclear which is the most ‘upstream’ triggering event arachidonic acid from phopholipids via cytosolic
or whether several occur at the same time. No phospholipase A (PLA ) following its activation by
2 2
sequential order or cascade has been identified but PLA -activating protein (Gronich et al., 1994). Some
2
several signaling events appear to be taking place IL-1-signaling events are prominent in different cells.
duringthefirst2–5minutes.Someofthebiochemical Postreceptor signaling mechanisms may therefore
changes associated with signal transduction are providecellularspecificity.Forexample,insomecells,
probably cell specific. Within 2 minutes, hydrolysis IL-1 is a growth factor and signaling is associated
of GTP, phosphatidylcholine, phosphatidylserine, or with serine/threonine phosphorylation of the MAP
phosphatidylethanolamine (Rosoff, 1989) and release kinase p42/44 in mesangial cells (Huwiler and
of ceramide by neutral (Schutze et al., 1994), not Pfeilschifter, 1994). The MAP p38 kinase, another
acidic, sphingomyelinase (Andrieu et al., 1994) have memberoftheMAPkinasefamily,isphosphorylated
beenreported.Ingeneral,multipleproteinphosphor- in fibroblasts (Freshney et al., 1994), as is the p54(cid:11)
ylations and activation of phosphatases can be MAP kinase in hepatocytes (Kuno et al., 1993).
observed within 5 minutes (Bomalaski et al., 1992)
and some are thought to be initiated by the release
Activation of MAP Kinases
of lipid mediators. The release of ceramide has at-
Following IL-1 Receptor Binding
tracted attention as a possible early signaling event
(Kolesnick and Golde, 1994). Phosphorylation of Multiple phosphorylations take place during the first
PLA -activating protein also occurs within the first 15 minutes following IL-1 receptor binding. Most
2
few minutes (Gronich et al., 1994) which would lead consistently, IL-1 activates protein kinases which
to a rapid release of arachidonic acid. Multiple and phosphorylate serine and threonine residues, targets
similar signaling events have also been reported oftheMAPkinasefamily.Anearlystudyreportedan
for TNF. IL-1-induced serine/threonine phosphorylation of a
OfspecialconsiderationtoIL-1signaltransduction 65kDa protein clearly unrelated to those phosphory-
istheunusualdiscrepancybetweenthelownumberof latedviaPKC(Matsushimaetal.,1987).Asreviewed
receptors (<10 in some cells) and the low concentra- by O’Neill (1995), prior to IL-1 activation of serine/
tions of IL-1 that can induce a biological response. threoninekinases,IL-1receptorbindingresultsinthe
This latter observation, however, may be clarified in phosphorylation of tyrosine residues (Freshney et al.,
studies on high-affinity binding with the IL-1R AcP 1994; Kracht et al., 1994). Tyrosine phosphorylation
IL-1 Receptor Type I 1593
inducedbyIL-1isprobablyduetoactivationofMAP Inhibition of p38 MAP Kinase
kinase kinase which then phosphorylates tyrosine
The target for pyridinyl imidazole compounds has
and threonine on MAP kinases.
been identified as a homolog of the HOG-1 family
Following activation of MAP kinases, there are
(Lee et al., 1994); its sequence is identical to that of
phosphorylations on serine and threonine residues
the p38 MAP kinase-activating protein 2 (Han et al.,
of the epidermal growth factor receptor, heat shock
1995). Inhibition of the p38 MAP kinase is highly
protein p27, myelin basic protein and serine 56 and
specificforreducingLPS-andIL-1-inducedcytokines
156 of (cid:12) casein, each of which has been observed in
(Leeetal.,1994).IL-1-inducedexpressionofHIV-1is
IL-1-stimulatedcells(Birdetal.,1991;Guesdonetal.,
suppressed by specific inhibition using pyridinyl
1993). TNF also activates these kinases. There are
imidazole compounds (Shapiro et al., 1998b). As
at least three families of MAP kinases. The p42/44
expected, this class of imidazoles also prevents the
MAP kinase family is associated with signal trans-
downstreamphosphorylationofhsp27(Cuendaetal.,
duction by growth factors including Ras/Raf-1signal
1995). Compounds of this class appear to be highly
pathways. In rat mesangial cells, IL-1 activates the
specific for inhibition of the p38 MAP kinase in that
p42/44 MAP kinase within 10 minutes and also
therewasnoinhibitionof12otherkinases.Usingone
increases de novo synthesis of p42 (Huwiler and
of these compounds, both hyperosmotic NaCl- and
Pfeilschifter, 1994).
IL-1(cid:11)-induced IL-8 synthesis was inhibited (Shapiro
andDinarello,1995).IthasbeenproposedthatMAP
p38 MAP Kinase Activation kinase-activatingprotein2isoneofthesubstratesfor
thep38MAPkinasesandthatMAPkinase-activating
The stress-activated protein kinase (SAPK), which is
protein 2 is the kinase which phosphorylates hsp 27
molecularly identified as Jun N-terminal kinase
(Cuenda et al., 1995).
(JNK), is phosphorylated in cells stimulated with
IL-1 (Stylianou and Saklatvala, 1998). In addition to
p42/44, two members of the MAP kinase family (p38 DOWNSTREAM GENE
and p54) have been identified as part of an IL-1
ACTIVATION
phosphorylation pathway and are responsible for
phosphorylatinghsp27(Freshneyetal.,1994;Kracht
Transcription factors activated
et al., 1994). In rabbit primary liver cells, IL-1
selectively activates JNK without apparentactivation
of p38 or p42 p38 MAP kinases (Finch et al., 1997). NF(cid:20)B and AP-1 (Muegge et al., 1989, 1993).
These MAP kinases are highly conserved proteins,
homologous to the HOG-1 stress gene in yeasts. In Genes induced
fact, when HOG-1 is deleted, yeasts fail to grow in
hyperosmotic conditions; however, the mammalian
See chapter on IL-1(cid:12).
gene coding for the IL-1-inducible p38 MAP kinase
(Krachtetal.,1994)canreconstitutetheabilityofthe
yeast to grow in hyperosmotic conditions (Galcheva- BIOLOGICAL CONSEQUENCES
Gargova et al., 1994). In cells stimulated with
OF ACTIVATING OR INHIBITING
hyperosmolar NaCl, LPS, IL-1, or TNF, indistin-
RECEPTOR AND
guishable phosphorylation of the p38 MAP kinase
takes place (Han et al., 1994). In human monocytes PATHOPHYSIOLOGY
exposed to hyperosmolar NaCl (375–425 mosmol/L),
IL-8, IL-1(cid:12), IL-1(cid:11), and TNF(cid:11) gene expression and Unique biological effects of
synthesis takes place, which is indistinguishable from
activating the receptors
that induced by LPS or IL-1 (Shapiro and Dinarello,
1995, 1997). Thus, the MAP p38 kinase pathways
involved in IL-1, TNF, and LPS signal transductions See Signal transduction.
sharecertainelementsthatarerelatedtotheprimitive
stress-induced pathway. The dependency of Rho Phenotypes of receptor knockouts
members of the GTPase family for IL-1-induced
and receptor overexpression mice
activation of p38 MAP kinases has been demon-
strated (Zhang et al., 1995). This latter observation
links the intrinsic GTPase domains of IL-1RI and Mice deficient in IL-1RI have been generated and
IL-1R AcP with activation of the p38 MAP kinase. show no abnormal phenotype in health and exhibit
1594 Charles A. Dinarello
normal homeostasis, similar to that observed in IL- that IL-1 contributes significantly to sepsis-induced
1(cid:12)-orIL-1(cid:11)-deficientmice(Horaietal.,1998;Zheng endothelial damage.
et al., 1995) but distinctly different from mice defi- Calvariae and humeri of IL-1RI-deficient mice
cient in IL-1Ra (Hirsch et al., 1996). Mice deficient were normal with respect to trabecular bone volume,
in IL-1RI do not exhibit significant disruption of osteoclast number, osteoclast surface, growth plate
reproduction aside from a somewhat reduced litter widths, and cortical thickness (Vargas et al., 1996).
size (Abbondanzo et al., 1996). In some laboratories, Parathyroid hormoneor TNF(cid:11)induced IL-6 mRNA
however, the body weights of the IL-1RI-deficient and protein levels in IL-1RI-deficient bone marrow
mice were 30% less than wild-type, whereas the stromal cells whereas IL-1(cid:11) had no effect. These
TNFRp55-deficient mice weighed 30% more than findings demonstrate that normal bone development
wild-typemiceofequivalentage(Vargasetal.,1996). in mice can occur in the absence of IL-1RI (Vargas
AlthoughIL-1(cid:11)isconstitutivelyexpressedintheskin, et al., 1996).
the barrier function of skin remains intact in mice IL-1RI-deficient mice have normal serum Ig levels
deficientinIL-1RI(Manetal.,1999).Similarly,mice and generate primary and secondary antibody
deficient in IL-1R AcP appear normal but have no responses equivalent to those of wild-type mice.
responses to IL-1 in vivo (Cullinan et al., 1998). SimilartoIL-1(cid:12)-deficientmice(Fantuzzietal.,1996),
However, cells deficient in IL-1R AcP have normal in response to a lethal challenge with D-galactosa-
binding of IL-1(cid:11) and IL-1Ra (binding to the IL-1RI mine plus LPS or high-dose LPS, IL-1RI-deficient
beingintact)buta70%reductioninbindingofIL-1(cid:12) mice are equivalent to wild-type mice. In addition,
(Cullinan et al., 1998). In these cells, there is no acute phase protein mRNA induction in IL-1RI-
biologicalresponsetoIL-1(cid:11)despitebindingofIL-1(cid:11). deficient and wild-type mice are similar (Glaccum
The results suggest that IL-1R AcP and not IL-1RI et al., 1997).
is required for IL-1(cid:12) binding and biological response In mice infected with Leishmania or following
to IL-1. immunization with keyhole limpet hemocyanin,
Mice injected with LPS have been studied. IL-1RI- IL-1RI deficiency resulted in a greater production
deficient mice exhibit the same decrease in hepatic of IL-4 and IL-10 compared to wild-type mice
lipase as do wild-type mice. However, injection of (Satoskar et al., 1998). In addition, wild-type mice
LPS directly into the eye of mice deficient in IL-1RI produced more IFN(cid:13) compared to IL-1RI-deficient
revealsadecrease inthenumber ofinfiltratingleuko- mice. These results suggest that IL-1 functions in
cytes whereas there was no decrease in mice deficient these models to downregulate the TH2 response,
in both TNF receptors (Rosenbaum et al., 1998). particularly IL-4.
IL-1RI-deficient mice failed to respond to IL-1 in a
variety of assays, including IL-1-induced IL-6 and
E-selectin expression and IL-1-induced fever (Labow
Human abnormalities
et al., 1997). Similar to IL-1(cid:12)-deficient mice, IL-1RI-
deficient mice had a reduced acute phase response
to turpentine. Also similar to IL-1(cid:12)-deficient mice A case of a cortisol-secreting adrenal adenoma
(Shornick et al., 1996), IL-1RI-deficient mice had a causing Cushing’s syndrome in a 62-year-old woman
reduced delayed-type hypersensitivity response and has been described. The patient exhibited the classic
were highly susceptible to infection by Listeria clinical and laboratory findings of Cushing’s syn-
monocytogenes. drome which abated once the tumor was removed.
Endotoxin-treated wild-type animals showed ex- Examination of the tissue revealed high expression of
tensive ultrastructural endothelial damage with most IL-1RI (Willenberg et al., 1998). Moreover, unlike
sections showing only denuded endothelium on the normal adrenal cells, the tumor did not respond to
luminal surface. IL-1RI-deficient mice injected with corticotropin-induced cortisol production but rather
endotoxin showed complete maintenance of endothe- responded to IL-1(cid:12) stimulation of cortisol produc-
lial structural integrity compared to endotoxin- tion.Incontrasttothepatient’stumor,otheradrenal
treated wild-type with ultrastructural morphology tumors responded to corticotropin-induced cortisol
appearing identical to those given saline vehicle production but not IL-1(cid:12). There was abundant
(Sutton et al., 1997). Also, no apparent correlation expression of the IL-1RI in the patient’s tumor
was observed be-tween serum IL-6 concentrations or but not in other tumors. It was concluded that the
serum nitric oxide levels and aortic endothelial unique expression of IL-1RI in this tumor and
damage. These studies confirm observations of induction of cortisol by IL-1(cid:12) resulted in the
endothelial cell protection with IL-1Ra and suggest pathological disease.
IL-1 Receptor Type I 1595
THERAPEUTIC UTILITY phaseItrialwithoutside-effectsorchangesinphysio-
logic, hematologic, or endocrinologic parameters.
Effect of treatment with soluble Thus, similar to infusions of IL-1Ra, soluble IL-1RI
appears safe and reinforces the conclusion that IL-1
receptor domain
does not have a role in homeostasis in humans.
Volunteers have been injected with LPS and
In Animal Studies
pretreated with soluble IL-1RI. The basis for these
The extracellular domain of the type I receptor has studies are that in animal models, blocking IL-1 with
been used in several models of inflammatory and IL-1Ra has reduced the severity of the response
autoimmune disease. Administration of murine IL- (reviewed in Dinarello, 1996). Pretreatment of
1sRItomicehasincreasedthesurvivalofheterotopic subjectswith10mg/kgofIL-1Rapriortointravenous
heart allografts and reduced the hyperplasic lymph endotoxin resulted in a statistically significant but
node response to allogeneic cells (Fanslow et al., modest decrease (40%) in circulating neutrophils
1990). In a rat model of antigen-induced arthritis, (Granowitz et al., 1993). Volunteers were also
localinstillationofthemurinesolubleIL-1RIreduced pretreated with soluble IL-1R type I or placebo and
joint swelling and tissue destruction (Dower et al., thenchallengedwithendotoxin.Therewerenoeffects
1994). When a dose of soluble receptor (1mg) was onfeverorsystemicsymptomsnoted.Althoughthere
instilled into the contralateral, unaffected joint, a was a decrease in the level of circulating IL-1(cid:12)
reductioninthedegreeoftissuedamagewasobserved compared to placebo-treated volunteers, there was
in the affected joint. These data suggest that the also a decrease in the level of circulating IL-1Ra
amount of soluble IL-1RI given in the normal, (p<0.001) due to complexing of the soluble receptor
contralateraljointwasactingsystemically.Inamodel to endogenous IL-1Ra (Preas et al., 1996). This was
of experimental autoimmune encephalitis, the soluble dose-dependent and resulted in a 43-fold decrease in
IL-1RI reduced the severity of this disease (Jacobs endotoxin-inducedIL-1Ra.Highdosesofsoluble IL-
et al., 1991). Administration of soluble IL-1RI to 1R type I were also associated with higher levels of
animals has also been reported to reduce the physio- circulating TNF(cid:11) and IL-8 as well as cell-associated
logicresponsetoLPS,acutelunginjury,anddelayed- IL-1(cid:12) (Preas et al., 1996). These results support the
typehypersensitivity(reviewedinDoweretal.,1994). concept that soluble IL-1R type I binds endogenous
However, there are also data suggesting that IL-1Raandreducesthebiologicaleffectivenessofthis
exogenous administration of soluble IL-1RI may be naturalIL-1receptorantagonistininhibitingIL-1.As
harmful. In mice, an i.v. injection of soluble IL-RI discussed below, patients with rheumatoid arthritis
aloneinducedarapidreleaseofcirculatingIL-1(cid:11),but treated with soluble IL-1R type I do not exhibit
notofTNF(cid:11)orIL-1(cid:12)(Neteaetal.,1999).Thesoluble improved clinical outcome and the mechanism is
receptor did not interfere with the IL-1(cid:11) assay. probably the binding of endogenous IL-1Ra with a
Treatment of mice with soluble IL-1RI improved the reduction in its biological role.
survivalduringalethalinfectionwithCandidaalbicans. Soluble IL-1R type was administered subcuta-
In the accelerated model of autoimmune diabetes neouslyto23patientswithactiverheumatoidarthritis
induced by cyclophosphamide in the nonobese dia- in a randomized, double-blind, two-center study.
betic (NOD) mouse, repeated injections with soluble Patients received subcutaneous doses of the receptor
IL-1R protected NOD mice from insulin-dependent at 25, 250, 500, or 1000mg/m2/day or placebo for 28
diabetes mellitus in a dose-dependent fashion; the consecutive days. Although four of eight patients
incidence of the diabetes was 53.3% in the mice receiving 1000mg/m2/day showed improvement in at
treated with 0.2mg/kg and only 6.7% in mice treated least one measure of disease activity, only one of
with 2mg/kg. However, none of the doses of the these four patients exhibited clinical improvement
solubleIL-1RIreducedtheextentofinsulitisinNOD (Drevlow et al., 1996). Similar to the placebo-treated
mice. Splenic lymphoid cells from NOD mice treated patients, lower doses of the receptor did not result in
with 2mg/kg soluble IL-1R for 5 consecutive days any improvement by acceptable criteria. Despite this
showed a normal distribution of mononuclear cell lack of clinical or objective improvement in disease
subsetsandmaintainedtheircapacitytosecreteIFN(cid:13) activity, cell surface monocyte IL-1(cid:11) expression in
and IL-2 (Nicoletti et al., 1994). all patients receiving the soluble IL-1R type I was
significantly reduced. Other parameters of altered
In Humans
immune function in common in patients with rheu-
Recombinant human soluble IL-1RI has been matoid arthritis also showed reduction. One possible
administered intravenously to healthy humans in a explanation for the lack of clinical response despite
1596 Charles A. Dinarello
efficacyinsuppressingimmuneresponsescouldbethe activity contributes to this conclusion. The potential
inhibition of endogenous IL-1Ra. This was observed disadvantage for using soluble IL-1 receptor type I
in volunteers receiving soluble IL-1R type I before therapy is the possibility that these receptors will
challenge by endotoxin (Preas et al., 1996). either prolong the clearance of IL-1 or bind the
A phase I trial of soluble IL-1RI was conducted in natural IL-1Ra.
patients with relapsed and refractory acute myeloid
leukemia. Soluble IL-1RI was well tolerated. Serum Host Defense Impairment with IL-1RI Blockade
levels of IL-1(cid:12), IL-6, and TNF(cid:11) did not change.
Micegivenanti-IL-1RIantibodyaremorevulnerable
Circulating levels of soluble IL-1RI were elevated
to lethal infection with Listeria, an obligate intracel-
360- and 25-fold after i.v. and s.c. administration,
lular bacterium (Havell et al., 1992). Similar findings
respectively.Therewerenocomplete,partialorminor
have been reported for TNFR blockade.
responses to treatment (Bernstein et al., 1999).
Human soluble IL-1RI inhibits HIV-1 expression
Why do Humans Respond to IL-1?
in acutely infected primary PBMCs and in the
chronically infected promonocytic cell line, U1. A Unlike other cytokine receptors, in cells expressing
phase I/II trial was conducted in HIV-1-infected both IL-1 type I and type II receptors, there is com-
individualswithCD4Tcellcounts <300/mL.Twelve petition to bind IL-1 first. This competition between
evaluable patients were enrolled at three increasing signaling and nonsignaling receptors for the same
doses of the soluble receptor injected three times a ligandappearsuniquetocytokinereceptors,although
week for 8 weeks, followed by a 4-week observation it exists for atrial natriuretic factor receptors
period (Takebe et al., 1998). Seven patients reported (Leitman et al., 1986). Since the type II receptor is
improvements in one or more symptoms, including more likely to bind to IL-1(cid:12) than IL-1(cid:11), this can
weight gain (3), improved energy level (4), decreased result in a diminished response to IL-1(cid:12). The soluble
diarrhea(1),decreasednightsweats(1),improvement forms of IL-1RI and IL-1RII circulate in healthy
in psoriatic arthritis (1), and improvement in a non- humans at molar concentrations which are 10- to 50-
specific chronic diffuse skin rash (1). No consistent fold greater than those of IL-1(cid:12) measured in septic
trends in absolute CD4 counts or percentages, quan- patients and 100-fold greater than the concentration
titative HIV-1 cultures, or serum p24 antigen, (cid:12) - of IL-1(cid:12) following intravenously administration
2
microglobulin, or triglyceride levels were observed. (Crownetal.,1991).Whydohumanshaveasystemic
The goal of any anti-IL-1 strategy is to prevent response to an infusion of IL-1(cid:11) (Smith et al., 1993)
IL-1 binding to surface receptors. Using soluble or IL-1(cid:12)? One concludes that binding of IL-1 to the
receptorstoblockIL-1activityindiseaseissimilarto soluble forms of IL-1R types I and II exhibits a slow
usingneutralizingantibodiesagainstIL-1anddistinct ‘on’ rate compared to the cell IL-1RI.
from using receptor blockade with IL-1Ra. Since the In addition, naturally occurring neutralizing anti-
molarconcentrationsofcirculatingIL-1indiseaseare bodies to IL-1(cid:11) are present in many subjects and
relatively low, pharmacologic administration of solu- probably reduce the activity of IL-1(cid:11). Despite the
ble IL-1RI to reach a 100-fold molar excess of the portfolioof solublereceptorsand naturallyoccurring
soluble receptor over that of IL-1 is feasible. The antibodies,IL-1producedduringdiseasedoes,infact,
human trial of soluble IL-1RI in delayed-hypersensi- trigger the type I receptor since in animals and
tivity reactions supports the notion that low doses humans,blockingreceptorsorneutralizingIL-1ame-
(100mg/patient) can have anti-inflammatory effects. liorates disease. These findings underscore the high
The fusion of two chains of extracellular domains of functional level of only a few IL-1 type I receptors.
thetypeIL-1RItotheFcportionofimmunoglobulin They also imply that the postreceptor triggering
enhances the binding of IL-1 over that of monomeric events are greatly amplified. It seems reasonable to
soluble IL-RI (Pitti et al., 1994) and may have a conclude that treating disease based on blocking IL-
greater plasma half-life compared to that of the 1Rneedstotakeintoaccounttheefficiencyofsofew
monomeric form. However, as shown in the study of type I receptors initiating a biological event.
soluble IL-1RI in rheumatoid arthritis, binding of the
endogenous IL-1Ra was associated with a worsening Effects of inhibitors (antibodies)
of the disease. In contrast to neutralizing IL-1 itself,
to receptors
the goal of receptor blockade requires the condition
of blocking all unoccupied IL-1 surface receptors
since triggering only a few evokes a response. AntibodiestothemouseIL-1RIblockIL-1responses
Receptor blockade is a formidable task and the large andreducetheseverityofdisease(Gershenwaldetal.,
amounts of IL-1Ra required to reduce disease 1990). In mice overexpressing TNF(cid:11) a rheumatoid