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7165.Dinarello Ch.A. - IL-1 Receptor Type II .pdf

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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: 303-315-3589, fax: 303-315-8054, e-mail: cdinare333@aol.com
DOI: 10.1006/rwcy.2000.15003.
SUMMARY
Structure
The extracellular domains of type II IL-1R are structurally related to those of the type I IL-1R; however,
the type II IL-1R is a decoy receptor in that the
primary ligand, IL-1, preferentially binds to this
receptor rather than the signaling receptor. As such,
in the presence of increasing expression of the type II
receptor on the cell surface, less IL-1 signaling takes
place. This is because the type II IL-1R lacks a
cytoplasmic domain capable of cell signal transduction. The type II IL-1R also exists in a shed form as a
soluble receptor. The soluble receptor has a high
affinity to bind IL-1 over that of IL-1 or IL-1Ra.
The soluble IL-1R type II is ideally suited for clinical
use because it has a high affinity for IL-1 and a low
affinity for IL-1Ra.
The extracellular domains of the IL-1RII are typical
of an Ig-like receptor in the fibroblast growth factor
family. The glycoprotein has three Ig-like domains in
the extracellular segment, a transmembrane domain,
and a short cytoplasmic domain (McMahon et al.,
1991).
BACKGROUND
GENE
Discovery
Accession numbers
The discovery of the IL-1 receptor type II (IL-1RII)
was made by in 1991 (McMahon et al., 1991). Others
also contributed to the discovery of this receptor
(Symons et al., 1991, 1993). The ability of IL-1 to
preferentially bind to B cells is also probably the
binding to the type II receptor (Scapigliati et al., 1989;
Ghiara et al., 1991).
The gene for the IL-1RII has been reported (Sims
et al., 1995).
Alternative names
Another name for the IL-1RII is the IL-1 `decoy'
receptor (Colotta et al., 1993, 1994).
Main activities and
pathophysiological roles
When IL-1 binds to the cell membrane, IL-1RII does
not signal. A soluble form of this receptor has been
described to act to reduce the biological effects of
IL-1 (Dower et al., 1994).
PROTEIN
Description of protein
IL-1RII has three Ig-like domains in the extracellular
segment, a transmembrane domain, and a short
cytoplasmic domain (McMahon et al., 1991). The
transmembrane segment is linked to a short cytoplasmic domain. In the rat, this cytoplasmic domain
1612 Charles A. Dinarello
is longer (Bristulf et al., 1994) but still does not signal.
In the human and mouse, IL-1RII has a short cytosolic domain consisting of 29 amino acids; in the rat,
there are an additional six charged amino acids
(Bristulf et al., 1994).
Relevant homologies and species
differences
There is considerable homology between the IL-1
receptor type I and IL-1RII in all species. Limited
homology between the IL-18-binding protein (Novick
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
protein binds IL-1 (Alcami and Smith, 1992; Spriggs
et al., 1992). These viruses also code for IL-18-binding
protein-like molecules.
Affinity for ligand(s)
The cell-bound IL-1RII does not appear to form a
complex with the IL-1R type I receptor (Slack et al.,
1993; Dower et al., 1994) nor does it transduce a
signal (Sims et al., 1993, 1994). The rank for the three
IL-1 ligands (IL-1, IL-1, and IL-1Ra) binding to
IL-1RII is IL-1 > IL-1 > IL-1Ra (Arend et al.,
1994; Dower et al., 1994; Sims et al., 1994). In some
cells, there is a discrepancy between the dissociation
constant of either form of IL-1 (usually 200�0 pM)
and concentrations of IL-1 which can elicit a biological response (10�0 fM). In cells expressing large
amounts of IL-1R AcP, the high-affinity binding of
the IL-1R/IL-1R AcP complex may explain why two
classes of binding have been observed. Human
recombinant 17 kDa IL-1 binds to cell surface and
soluble type I receptors with approximately the same
affinity (200�0 pM); however, binding to surface
and soluble type II receptors is nearly 100-fold less
(30 and 10 nM, respectively).
Of the three members of the IL-1 family, IL-1 has
the lowest affinity for the cell-bound form of IL-1RI
(500 pM�nM). By comparison, IL-1 binds more
avidly to the nonsignal transducing type II receptor
(100 pM). IL-1 binding to the soluble form of the
IL-1RI is lower than that to the cell-bound receptor.
However, the most dramatic differences in IL-1
binding can be seen at the level of the soluble form of
the type II receptor. Of the three ligands, the most
avid binding is that of mature IL-1 (500 pM). IL-1
binding to the soluble IL-1RII is nearly irreversible
due to a long dissociation rate (2 hours) (Arend et al.,
1994; Dower et al., 1994; Symons et al., 1994).
Moreover, precursor IL-1 also preferentially binds
to the soluble form of IL-1RII (Symons et al., 1991,
1993).
Cell types and tissues expressing
the receptor
The primary cells expressing the IL-1RII are
monocytes, macrophages, neutrophils, B lymphocytes, myelomonocytic leukemia cells, and hairy cell
leukemic cells.
Regulation of receptor expression
Increased surface expression of IL-1RII reduces the
biological response to IL-1 (Colotta et al., 1993,
1994). Gene expression of the IL-1RII is under the
control of two promoters, each of which controls the
usage of a divided first exon (exon 1A or 1B) (Vannier
et al., 1995). Early studies using B cells, monocytes,
or bone marrow cells (type II receptor-bearing cells)
demonstrated that hematopoietic growth factors,
dexamethasone, and PGE2 increase the number of
IL-1-binding sites. Surface expression of IL-1RII is
upregulated on neutrophils exposed to dexamethasone and IL-4 (Colotta et al., 1993) and on monocytes
or B cell lines exposed to dexamethasone (Dower
et al., 1994). These observations have been confirmed
using gene expression in different cell lines (Vannier
et al., 1995). A transcription factor called PU.1, which
is present in cells of hematopoietic origin, is required
for expression of IL-1RII. In patients with bacterial
sepsis, elevated IL-1RII expression has been observed
on neutrophils (Fasano et al., 1991). Although IL-1
itself downregulates gene and surface expression of
IL-1RI, IL-1 upregulates gene and surface expression
of the IL-1RII on an insulinoma cell line (Bristulf
et al., 1994).
Release of soluble receptors
Unlike soluble TNF receptors, it is unknown whether
the soluble form of IL-1RII acts as a carrier for IL-1
and prolongs its half-life in the circulation. It is likely
that as cell-bound IL-1RII increases, there is a comparable increase in soluble forms (Giri et al., 1990).
Similar to soluble receptors for TNF, the extracellular
domains of the type II IL-1R are found as `soluble'
molecules in the circulation and urine of healthy
IL-1 Receptor Type II 1613
subjects and in inflammatory synovial and other
pathologic body fluids (Symons et al., 1993, 1994;
Arend et al., 1994; Sims et al., 1994; Barak et al.,
1996). In healthy humans, the circulating concentrations of the soluble IL-1RII are 100�0 pM.
Elevated levels of the soluble IL-1RII are found in
the circulation of patients with sepsis (Giri et al.,
1994) and in the synovial fluid of patients with active
rheumatoid arthritis (Arend et al., 1994) and in
patients with hairy cell leukemia (Barak et al., 1996).
In patients undergoing aorta resection, crossclamping
of the aorta results in significant ischemia and a
dramatic release of soluble IL-1RII (Pruitt et al.,
1996). High-dose IL-2 therapy induces soluble IL1RII (Orencole et al., 1995).
LPS causes rapid shedding of the IL-1 type II. This
effect of LPS is reduced by inhibition of metalloprotease. Following LPS, monocytes exhibited a reduction in steady-state mRNA levels (Penton-Rol et al.,
1999). Chemoattractants also cause a rapid release
of the extracellular domain of the IL-1RII from
myelomonocytic cells within a few minutes following
exposure (Mantovani et al., 1998). This induction of
release of the decoy receptor suggests an early event
in inflammation to limit the cascade. Inhibitors of
matrix metalloproteases such as hydroxamic acid
inhibit the release of the extracellular domain of
IL-1RII (Orlando et al., 1997). These protease inhibitors also reduced the slow release of soluble IL-1RII
from monocytes and neutrophils and from cells
stimulated with dexamethasone, TNF, chemoattractants, or phorbol myristate acetate (PMA). Inhibitors
of other protease classes did not affect release.
Inhibitors of serine proteases increased the molecular
size of the released form of IL-1RII from 45 to
60 kDa (Orlando et al., 1997).
SIGNAL TRANSDUCTION
Associated or intrinsic kinases
Because the IL-1RII has no significant cytoplasmic
domain, there are no kinases intrinsic to the receptor.
See reveiw of Martin and Falk (1997).
Cytoplasmic signaling cascades
The IL-1RII does not signal and serves only to bind
IL-1 (preferentially IL-1) and prevent signaling by
IL-1 binding to the type I receptor (Colotta et al.,
1994).
BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
RECEPTOR AND
PATHOPHYSIOLOGY
Unique biological effects of
activating the receptors
The type II receptor appears to act as `decoy'
molecule, particularly for IL-1. The receptor binds
IL-1 tightly, thus preventing binding to the signaltransducing type I receptor (Colotta et al., 1993). It is
the lack of a signal-transducing cytosolic domain that
makes the type II receptor a functionally negative
receptor. For example, when the extracellular portion
of the type II receptor is fused to the cytoplasmic
domain of the type I receptor, a biological signal
occurs (Heguy et al., 1993). The extracellular portion
of the type II receptor is found in body fluids, where it
is termed IL-1 soluble receptor type II. A proteolytic
cleavage of the extracellular domain of the IL-1RII
from the cell surface is the source of the soluble
receptor.
Phenotypes of receptor knockouts
and receptor overexpression mice
Constructs encoding IL-1RII were transfected into
U937 cells. Gene transfer resulted in receptor
numbers (approximately 103/cell) of the same order
of magnitude as that found in normal myelomonocytic cells. Transfer of IL-1RII reduced responsiveness to IL-1 (Penton-Rol et al., 1997). Mice
overexpressing IL-1RII or deficient in IL-1RII are
not reported to date.
THERAPEUTIC UTILITY
Effect of treatment with soluble
receptor domain
Because soluble IL-1RII binds IL-1 so avidly, a
considerable therapeutic use is likely.
Effects of inhibitors (antibodies)
to receptors
In general, antibodies to IL-1RI block IL-1-mediated
activities in vitro and in vivo, whereas antibodies
1614 Charles A. Dinarello
specific for the IL-1RII have no effect. An antibody
(ALVA 42) which recognizes and subunits of
HLA-DR (Gayle et al., 1994) also binds to cells
expressing type II receptors (Ghiara et al., 1991). The
ability of this antibody to inhibit IL-1-mediated
effects in vivo may be due to inhibition of IL-1induced production of IL-1. For example, anti-HLADR monoclonal antibodies stimulate the production
of IL-1 by macrophages and enhance (or suppress)
IL-1 induced by either superantigens or LPS.
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