IL-1 Receptor Type II

6 Pages·0.066 MB·English

by  Dinarello Ch.A.

IL-1 Receptor Type II
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.2000.15003.
SUMMARY Structure
The extracellular domains of type II IL-1R are struc- The extracellular domains of the IL-1RII are typical
turally related to those of the type I IL-1R; however, of an Ig-like receptor in the fibroblast growth factor
the type II IL-1R is a decoy receptor in that the family. The glycoprotein has three Ig-like domains in
primary ligand, IL-1(cid:12), preferentially binds to this the extracellular segment, a transmembrane domain,
receptor rather than the signaling receptor. As such, and a short cytoplasmic domain (McMahon et al.,
in the presence of increasing expression of the type II 1991).
receptor on the cell surface, less IL-1 signaling takes
place. This is because the type II IL-1R lacks a
Main activities and
cytoplasmic domain capable of cell signal transduc-
tion.ThetypeIIIL-1Ralsoexistsinashedformasa pathophysiological roles
soluble receptor. The soluble receptor has a high
affinity to bind IL-1(cid:12) over that of IL-1(cid:11) or IL-1Ra.
When IL-1 binds to the cell membrane, IL-1RII does
The soluble IL-1R type II is ideally suited for clinical
not signal. A soluble form of this receptor has been
use because it has a high affinity for IL-1(cid:12) and a low
described to act to reduce the biological effects of
affinity for IL-1Ra.
IL-1(cid:12) (Dower et al., 1994).
BACKGROUND GENE
Discovery Accession numbers
The discovery of the IL-1 receptor type II (IL-1RII) The gene for the IL-1RII has been reported (Sims
was made by in 1991 (McMahon et al., 1991).Others et al., 1995).
also contributed to the discovery of this receptor
(Symons et al., 1991, 1993). The ability of IL-1(cid:12) to
preferentially bind to B cells is also probably the PROTEIN
bindingtothetypeIIreceptor(Scapigliatietal.,1989;
Ghiara et al., 1991). Description of protein
IL-1RII has three Ig-like domains in the extracellular
Alternative names
segment, a transmembrane domain, and a short
cytoplasmic domain (McMahon et al., 1991). The
Another name for the IL-1RII is the IL-1 ‘decoy’ transmembrane segment is linked to a short cyto-
receptor (Colotta et al., 1993, 1994). plasmic domain. In the rat, this cytoplasmic domain
1612 Charles A. Dinarello
islonger(Bristulfetal.,1994)butstilldoesnotsignal. 1994; Dower et al., 1994; Symons et al., 1994).
In the human and mouse, IL-1RII has a short cyto- Moreover, precursor IL-1(cid:12) also preferentially binds
solic domain consisting of 29 amino acids; in the rat, to the soluble form of IL-1RII (Symons et al., 1991,
there are an additional six charged amino acids 1993).
(Bristulf et al., 1994).
Cell types and tissues expressing
Relevant homologies and species
the receptor
differences
The primary cells expressing the IL-1RII are
There is considerable homology between the IL-1 monocytes, macrophages, neutrophils, B lympho-
receptor type I and IL-1RII in all species. Limited cytes, myelomonocytic leukemia cells, and hairy cell
homologybetweentheIL-18-bindingprotein(Novick leukemic cells.
et al., 1999) and the IL-1RII exists. Vaccinia and
cowpox virus genes encode for a protein with a high
amino acid homology to the type II receptor and this
Regulation of receptor expression
proteinbindsIL-1(cid:12)(AlcamiandSmith,1992;Spriggs
etal.,1992).ThesevirusesalsocodeforIL-18-binding
Increased surface expression of IL-1RII reduces the
protein-like molecules.
biological response to IL-1 (Colotta et al., 1993,
1994). Gene expression of the IL-1RII is under the
Affinity for ligand(s) control of two promoters, each of which controls the
usageofadividedfirstexon(exon1Aor1B)(Vannier
et al., 1995). Early studies using B cells, monocytes,
The cell-bound IL-1RII does not appear to form a
or bone marrow cells (type II receptor-bearing cells)
complex with the IL-1R type I receptor (Slack et al.,
demonstrated that hematopoietic growth factors,
1993; Dower et al., 1994) nor does it transduce a
dexamethasone, and PGE increase the number of
signal(Simsetal.,1993,1994).Therankforthethree 2
IL-1-binding sites. Surface expression of IL-1RII is
IL-1 ligands (IL-1(cid:11), IL-1(cid:12), and IL-1Ra) binding to
upregulated on neutrophils exposed to dexametha-
IL-1RII is IL-1(cid:12)>IL-1(cid:11)>IL-1Ra (Arend et al.,
soneandIL-4(Colottaetal.,1993)andonmonocytes
1994; Dower et al., 1994; Sims et al., 1994). In some
or B cell lines exposed to dexamethasone (Dower
cells, there is a discrepancy between the dissociation
etal., 1994).These observationshavebeen confirmed
constant of either form of IL-1 (usually 200–300pM)
using gene expression in different cell lines (Vannier
and concentrations of IL-1 which can elicit a bio-
etal.,1995).AtranscriptionfactorcalledPU.1,which
logical response(10–100fM). Incells expressinglarge
is present in cells of hematopoietic origin, is required
amounts of IL-1R AcP, the high-affinity binding of
for expression of IL-1RII. In patients with bacterial
the IL-1R/IL-1R AcP complex may explain why two
sepsis,elevatedIL-1RIIexpressionhasbeenobserved
classes of binding have been observed. Human
on neutrophils (Fasano et al., 1991). Although IL-1
recombinant 17kDa IL-1(cid:11) binds to cell surface and
itself downregulates gene and surface expression of
soluble type I receptors with approximately the same
IL-1RI, IL-1 upregulates gene and surface expression
affinity (200–300pM); however, binding to surface
of the IL-1RII on an insulinoma cell line (Bristulf
and soluble type II receptors is nearly 100-fold less
et al., 1994).
(30 and 10nM, respectively).
OfthethreemembersoftheIL-1family,IL-1(cid:12) has
the lowest affinity for the cell-bound form of IL-1RI
Release of soluble receptors
(500pM–1nM). By comparison, IL-1(cid:12) binds more
avidly to the nonsignal transducing type II receptor
(100pM). IL-1(cid:12) binding to the soluble form of the UnlikesolubleTNFreceptors,itisunknownwhether
IL-1RI is lower than that to the cell-bound receptor. thesolubleformofIL-1RIIactsasacarrierforIL-1(cid:12)
However, the most dramatic differences in IL-1(cid:12) andprolongsitshalf-life inthe circulation. Itis likely
bindingcanbeseenatthelevelofthesolubleformof that as cell-bound IL-1RII increases, there is a com-
the type II receptor. Of the three ligands, the most parable increase in soluble forms (Giri et al., 1990).
avid binding is that of mature IL-1(cid:12) (500pM). IL-1(cid:12) SimilartosolublereceptorsforTNF,theextracellular
binding to the soluble IL-1RII is nearly irreversible domains of the type II IL-1R are found as ‘soluble’
duetoalongdissociationrate(2hours)(Arendetal., molecules in the circulation and urine of healthy
IL-1 Receptor Type II 1613
subjects and in inflammatory synovial and other BIOLOGICAL CONSEQUENCES
pathologic body fluids (Symons et al., 1993, 1994;
OF ACTIVATING OR INHIBITING
Arend et al., 1994; Sims et al., 1994; Barak et al.,
1996). In healthy humans, the circulating concentra- RECEPTOR AND
tions of the soluble IL-1RII are 100–200pM. PATHOPHYSIOLOGY
Elevated levels of the soluble IL-1RII are found in
the circulation of patients with sepsis (Giri et al.,
Unique biological effects of
1994) and in the synovial fluid of patients with active
activating the receptors
rheumatoid arthritis (Arend et al., 1994) and in
patients with hairy cell leukemia (Barak et al., 1996).
Inpatientsundergoingaortaresection,crossclamping The type II receptor appears to act as ‘decoy’
of the aorta results in significant ischemia and a molecule, particularly for IL-1(cid:12). The receptor binds
dramatic release of soluble IL-1RII (Pruitt et al., IL-1(cid:12) tightly, thus preventing binding to the signal-
1996). High-dose IL-2 therapy induces soluble IL- transducingtypeIreceptor(Colottaetal.,1993).Itis
1RII (Orencole et al., 1995). thelackofasignal-transducingcytosolicdomainthat
LPScausesrapidsheddingoftheIL-1typeII.This makes the type II receptor a functionally negative
effect of LPS is reduced by inhibition of metallopro- receptor.Forexample,whentheextracellularportion
tease. Following LPS, monocytes exhibited a reduc- of the type II receptor is fused to the cytoplasmic
tion in steady-state mRNA levels (Penton-Rol et al., domain of the type I receptor, a biological signal
1999). Chemoattractants also cause a rapid release occurs (Heguy et al., 1993). The extracellular portion
of the extracellular domain of the IL-1RII from ofthetypeIIreceptorisfoundinbodyfluids,whereit
myelomonocytic cells within a few minutes following is termed IL-1 soluble receptor type II. A proteolytic
exposure (Mantovani et al., 1998). This induction of cleavage of the extracellular domain of the IL-1RII
release of the decoy receptor suggests an early event from the cell surface is the source of the soluble
in inflammation to limit the cascade. Inhibitors of receptor.
matrix metalloproteases such as hydroxamic acid
inhibit the release of the extracellular domain of
Phenotypes of receptor knockouts
IL-1RII(Orlandoetal.,1997).Theseproteaseinhibi-
tors also reduced the slow release of soluble IL-1RII and receptor overexpression mice
from monocytes and neutrophils and from cells
stimulated with dexamethasone, TNF, chemoattrac- Constructs encoding IL-1RII were transfected into
tants,orphorbolmyristateacetate(PMA).Inhibitors U937 cells. Gene transfer resulted in receptor
of other protease classes did not affect release. numbers (approximately 103/cell) of the same order
Inhibitors of serine proteases increased the molecular of magnitude as that found in normal myelomono-
size of the released form of IL-1RII from 45 to cytic cells. Transfer of IL-1RII reduced responsive-
60kDa (Orlando et al., 1997). ness to IL-1 (Penton-Rol et al., 1997). Mice
overexpressing IL-1RII or deficient in IL-1RII are
not reported to date.
SIGNAL TRANSDUCTION
THERAPEUTIC UTILITY
Associated or intrinsic kinases
Effect of treatment with soluble
Because the IL-1RII has no significant cytoplasmic receptor domain
domain,therearenokinasesintrinsictothereceptor.
See reveiw of Martin and Falk (1997).
Because soluble IL-1RII binds IL-1(cid:12) so avidly, a
considerable therapeutic use is likely.
Cytoplasmic signaling cascades
Effects of inhibitors (antibodies)
to receptors
The IL-1RII does not signal and serves only to bind
IL-1 (preferentially IL-1(cid:12)) and prevent signaling by
IL-1 binding to the type I receptor (Colotta et al., In general, antibodies to IL-1RI block IL-1-mediated
1994). activities in vitro and in vivo, whereas antibodies
1614 Charles A. Dinarello
specific for the IL-1RII have no effect. An antibody interleukin-1 induction of gene expression in T cells. J. Biol.
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