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5961.Barry Bresnihan Jean-Michel Dayer - IL-1Ra (2001 Informa Healthcare).pdf

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Danielle Burger* and Jean-Michel Dayer
Division of Immunology and Allergy, Department of Internal Medicine, University Hospital, CH-1211,
Geneva 14, Switzerland
* corresponding author tel: 41-22-372-9376, fax: 41-22-372-9369, e-mail:
DOI: 10.1006/rwcy.2000.04002.
Inflammation is an important homeostatic mechanism that limits the effects of infectious agents.
However, inflammation might be self-damaging and
therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a critical
mediator of the inflammatory response, playing an
important part in the development of pathologic
conditions leading to chronic inflammation. Although
IL-1 production may be downmodulated or its effect
limited by so-called anti-inflammatory cytokines,
IL-1 inflammatory effects are inhibited and can be
abolished (in vitro) by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra).
To date, three forms of IL-1Ra have been identified, one soluble form and two intracellular forms,
referred to as sIL-1Ra, icIL-1RaI, and icIL-1RaII,
respectively. Although sIL-1Ra functions obviously
as an IL-1 inhibitor by competitively binding to IL-1
receptor without inducing signal transduction, the
functions of icIL-1RaI and icIL-1RaII remain to be
determined. The three forms of IL-1Ra are transcribed from the same gene, two different promoters
regulating the transcription of sIL-1Ra and icIL1RaI. In mice, sIL-1Ra is predominantly found in
peripheral blood cells, the lung, spleen, and liver,
while icIL-1RaI is mainly found in the skin. IL-1Ra
knockout mice display growth retardation after
weaning and an increased susceptibility to endotoxininduced injury and collagen-induced arthritis, suggesting that IL-1Ra plays an important part in both
health and pathologic conditions. IL-1Ra is produced
by hepatic cells as an acute phase protein. The
circulating blood levels of sIL-1Ra are low in normal
condition and elevated in individuals with allele 2 polymorphism and in several human infectious, autoimmune, and chronic inflammatory diseases, as well as
in numerous experimental models of diseases in
animals. Because of its beneficial effects in many
animal disease models, IL-1Ra has been used as therapeutic agent in human patients. IL-1Ra has failed to
show beneficial effects in septic shock but seems to
improve the condition of rheumatoid arthritis patients.
Interleukin 1 receptor antagonist (IL-1Ra) is a
member of the IL-1 family. Three forms of IL-1Ra
have been described, two of them being expressed as
intracellular proteins (icIL-1RaI and icIL-1RaII) and
one being secreted (sIL-1Ra). The three forms of IL1Ra result from the same gene. The function(s) of the
intracellular forms of IL-1Ra are still elusive whereas
sIL-1Ra binds competitively to IL-1 receptor I
without inducing signal transduction and thus inhibits IL-1 and IL-1 actions.
An IL-1 inhibitory activity was first observed in the
urine of febrile patients (Balavoine et al., 1986).
Subsequently this activity was further attributed to
sIL-1Ra, which blocks IL-1 binding to its receptor
(Seckinger et al., 1987). sIL-1Ra cDNA was cloned
from a human monocyte library (Eisenberg et al.,
1990). Thereafter, sIL-1Ra was found to be produced
by many other cells including neutrophils, fibroblasts,
corneal epithelial cells, and microglial cells. Indeed,
sIL-1Ra production is inducible in most cell types.
Natural sIL-1Ra is a 22±26 kDa glycoprotein
(Seckinger et al., 1987; Hannum et al., 1990; Mazzei
et al., 1990), whose recombinant 17 kDa form retains
full IL-1-inhibitory capacity (Carter et al., 1990;
320 Danielle Burger and Jean-Michel Dayer
Eisenberg et al., 1990). Since it potently inhibits the
various effects of IL-1, sIL-1Ra is considered an
important regulator of the inflammatory and overall
immune response mediated by IL-1. sIL-1Ra was
soon regarded as a potential marker of disease
severity (Prieur et al., 1987) and a therapeutic tool
(Seckinger et al., 1990). icIL-1RaI was also cloned
from a human monocyte library (Haskill et al., 1991).
Natural and recombinant icIL-1RaI binds to the IL-1
receptor I with a similar affinity to sIL-1Ra in vitro
(Gruaz-Chatellard et al., 1991; Haskill et al., 1991).
icIL-1RaI is constitutively expressed in keratinocytes
and epithelial cells (Arend, 1993; Arend et al., 1998).
Another putative intracellular form of IL-1Ra was
identified by polymerase chain reaction on mRNA
from human polymorphonuclear cells (Muzio et al.,
1995). However, the protein product of this high
molecular weight icIL-1Ra mRNA form has never
been detected. More recently, a 16 kDa icIL-1Ra was
detected by western blot analysis of LPS-stimulated
human neutrophils, monocytes, and the human hepatoma cell line HepG2 (Gabay et al., 1997b; Malyak
et al., 1998). This low molecular weight form of icIL1Ra is now referred to as icIL-1RaII. Furthermore,
a variant cDNA species containing an additional 171
nucleotides within the icIL-1RaI cDNA, that interrupts the coding region, was recently described
(Weissbach et al., 1998). This mRNA variant was
found to be expressed in keratinocytes and human
articular cartilage. Translation is likely to be initiated
at an alternate Met codon other than that utilized for
icIL-1RaI, suggesting that this mRNA variant encodes
a novel polypeptide. The function(s) of icIL-1Ra isoforms remain(s) unclear.
Alternative names
IL-1Ra was also known as IL-1 receptor antagonist
protein (IRAP), but it is now currently referred to as
IL-1Ra or sIL-1Ra (secreted IL-1Ra) and its intracellular forms as icIL-1RaI and icIL-1RaII.
Mature human sIL-1Ra is a 152 amino acid residue
protein which is generated by the cleavage of a 25
amino acid hydrophobic signal sequence from a
cytoplasmic precursor of 177 amino acid residues.
Although IL-1Ra, IL-1, and IL-1 genes seem to
have arisen through duplication and divergence of a
common ancestral gene, sIL-1Ra displays no more
than 19% and 26% amino acid sequence homology
with IL-1 and IL-1, respectively. However,
sIL-1Ra sequence was conserved during evolution,
displaying > 75% homology in human, rat, rabbit,
mouse, bovine, and horse sIL-1Ra. sIL-1Ra interacts
with the same receptors as IL-1 and IL-1
suggesting structural rather than sequence similarities
between these cytokines. It has been proposed that
sIL-1Ra binds to the IL-1 receptor I through one
interacting domain as compared with two such
domains on IL-1 and IL-1. The lack of a
receptor-interacting domain might be the cause of
the lack of signal transduction upon binding of sIL1Ra to IL-1 receptor I (for review see Lennard, 1995).
Main activities and
pathophysiological roles
sIL-1Ra competitively binds the IL-1 receptor I
without inducing signal transduction. It is therefore
likely that sIL-1Ra regulates (inhibits) cellular
functions affected by IL-1 and/or IL-1. The
function(s) of intracellular forms of IL-1Ra are less
obvious. Some hypotheses were recently reviewed
(Arend et al., 1998) claiming that icIL-1Ra might
counteract intracellular IL-1 activities and destabilize and/or degrade mRNAs induced by IL-1.
However the latter functions remain to be demonstrated. More recently, it has been shown that resting
and cytokine-stimulated human pulmonary epithelial
cells release icIL-1RaI in the extracellular space,
where it can antagonize cell surface IL-1R (Levine
et al., 1997). Therefore, icIL-1Ra might be an epithelial
store of IL-1Ra liable to immediate release upon
stimulation. Furthermore, the expression of icIL1RaI in Caco-2 cells decreased IL-1-induced IL-8
secretion (Bocker et al., 1998). Whether icIL-1RaI is
released by the latter cells remains to be determined.
Accession numbers
The IL-1Ra gene is referred to as IL-1RN. The
sequence of human IL-1RN, bases 1±33,414, is
accessible in GenBank at number U65590. cDNA
sequences are accessible at number M63099 (human
sIL-1Ra) and X84348 (human icIL-1RaI) and
X52015, X64532, X53296, and M55646. Mouse IL1RN is accessible at number MGI:92197.
Chromosome location
Human IL-1RN has been mapped in the long arm of
chromosome 2 at bands q14-21 (Steinkasserer et al.,
one minor and two major sites, 14, 15, and 16
nucleotides, respectively, upstream to the cDNA
sequence. icIL-1RaII is derived from both icIL-1RaI
and sIL-1Ra mRNA by alternative translation
initiation from the second 50 ATG (Malyak et al.,
A variable number of tandem repeats polymorphism has been described in intron 2 of the IL-1Ra gene
(Tarlow et al., 1993). Allele 2 of this polymorphism is
associated with the severity of many chronic inflammatory diseases (Table 1), although the mechanism of
this association remains elusive. Furthermore, carriage of at least one copy of the A2 allele was found to
be associated with reduced bone loss at the spine in
early postmenopausal patients (Keen et al., 1998). In
normal human subjects, IL-1Ra allele 2 has a clear
influence on IL-1Ra circulating levels, i.e. its carrier
individuals had 10-fold higher levels (745 ng/mL) than
the noncarrier individuals (627 pg/mL). This also
required the presence of the IL-1 -511 allele 2 or
absence of the IL-1 +3953 allele 2, indicating that
the IL-1 gene participates in the regulation of IL1Ra production in vivo (Hurme and Santtila, 1998).
Reciprocally, the presence of the IL-1Ra allele 2 is
associated with enhanced IL-1 production in
mononuclear cells in vitro (Santtila et al., 1998).
The activity of sIL-1Ra promoter is highly
controlled by tissue restricted factor(s), being
inactivated in T cells (Jurkat), B cells (Raji), and
epithelial cells (HeLa, HT29) (Smith et al., 1992;
Butcher et al., 1994). Furthermore, the sIL-1Ra gene
is not constitutively expressed in resting or unstimulated monocytes, and established myeloid cell lines
such as THP1, in contrast to macrophages. Promoter
elements controlling the induction of human sIL-1Ra
1993). Mouse IL-1RN has also been mapped at
chromosome 2 (10.00 cM) (Zahedi et al., 1991).
Relevant linkages
Human IL-1 and IL-1 genes (IL-1A and IL-1B) are
also located in the long arm of chromosome 2. There
are only 75 kb between IL-1A and IL-1B and 200 kb
between IL-1B and IL-1RN. The genes of the
mouse IL-1 family are mapped in chromosome 2
but IL-1RN is far from IL-1A and IL-1B which are
closely linked. In the human system the IL-1 receptor
genes map in chromosome 2 close to the IL-1 gene
cluster, whereas this is not the case in the mouse.
Regulatory sites and corresponding
transcription factors
sIL-1Ra, icIL-1RaI, and icIL-1RaII are translates
originating from the same gene (Figure 1). sIL-1Ra
and icIL-1RaI are produced by the alternative splicing of two different exons 1: 1s and 1ic. Exon 1ic is
located upstream of exon 1s. Exon 1ic splices into
exon 1s excluding a large proportion of the leader
peptide sequence (Butcher et al., 1994). The transcription of icIL-1Ra and sIL-1Ra is controlled by
two different promoters, Pic and Ps, respectively. Pic
is located upstream of exon 1ic and Ps is located
upstream of exon 1s, in the 9.4 kb intron which
separates exon 1ic from 1s. Three transcription start
sites have been identified for human sIL-1Ra mRNA,
Figure 1 IL-1Ra isoforms are generated from the same gene. icIL-1Ra is
produced by splicing of exon 1ic into exon 1s excluding a large proportion of
the leader peptide sequence (dashed zone). The production of sIL-1Ra is
controlled by promoter Ps. sIL-1Ra pro-peptide is processed and glycosylated prior to secretion.
Primary RNA
Intracellular protein
Secreted protein
322 Danielle Burger and Jean-Michel Dayer
Table 1
Association of two allele repeat (IL1RN*2) with inflammatory diseases
Associated diseases
Alopecia aerata
Cork et al. (1995), Tarlow et al. (1994)
Systemic lupus erythematosus
Suzuki et al. (1997), Blakemore et al. (1994)
Tarlow et al. (1997)
Diabetic nephropathy
Blakemore et al. (1996)
Relapsing/remitting multiple sclerosis
de la Concha et al. (1997)
Liu et al. (1997)
SjoÈgren's syndrome
Perrier et al. (1998)
Nonassociated diseases
Graves' disease
Muhlberg et al. (1998), Cuddihy and Bahn, (1996)
Ulcerative colitis
Hacker et al. (1997), Bioque et al. (1996)
Rheumatoid arthritis
Tarlow et al. (1994)
Crohn's disease
Mansfield et al. (1994)
were identified in mouse (RAW 264.7) and human
(THP1) myeloid cell lines (Smith et al., 1992; Butcher
et al., 1994). sIL-1Ra promoter is active in transfected
cell lines, suggesting a dysregulation in such systems.
Nucleotide deletion downstream of -294 had no
significant effect on promoter activity, although this
region might contain elements required for the
inducible activation of sIL-1Ra transcription in
myeloid cells. Indeed, most proximal 294 bp of the
human sIL-1Ra promoter are sufficient for full basal
activity and LPS responsiveness. Four LPS-responsive elements (LRE) have been identified in the sIL1Ra promoter. One LRE masking the response to
LPS is located between -294 and -250 (INH). Three
other positive-acting sites were identified between 250 and -200 (LRE3), -200 and -148 (LRE2), and -93
and -84 (LRE1) (Smith et al., 1994). LRE1, LRE2,
and LRE3 exhibited cooperativity in mediating the
responses to LPS. LRE1 was identified as an NFBbinding site. The transcription factors binding to
LRE2 and LRE3 remain to be identified. Recently,
two PU.1-binding sites were identified (Smith et al.,
1998), one of which centered at -230 whose mutation
resulted in a 50% decrease in LPS-responsive
promoter activity. The other PU.1-binding site,
which partially overlapped the NFB site, was
revealed to be a novel composite NFB/PU.1/GAbinding protein-binding site. Both PU.1-binding sites
are major responsive elements for LPS-induced sIL1Ra gene expression. Two STAT-binding elements
(SBEs) were identified in a region between -250 and 200. Upon IL-4 activation of monocyte-macrophages,
STAT6 binds to the more distal SBE, inducing
transcriptional activation of sIL-1Ra gene (Ohmori et
al., 1996).
In transfection studies, a promoter/luciferase fusion
construct containing 4.5 kb of the 50 flanking
sequence of the human icIL-1Ra gene exhibited a
pattern of expression in epithelial cell lines and
macrophage cell lines similar to that of the
endogenous icIL-1Ra gene (Jenkins et al., 1997).
Mutants of the latter promoter construct indicated
that the constitutive expression in epithelial cells was
under the control of three positively acting regions
located between bases -4525 to -1438, -288 to -56, and
-156 to -49. In contrast, basal activity of the icIL1RaI promoter in transfected but unstimulated RAW
264.7 cells was under the control of a weak inhibitory
region located between -4525 and -1438 bp and a
strong positive element between -156 and -49.
Induction of icIL-1Ra transcription by LPS in
RAW 264.7 cells was regulated by strong positively
acting DNA regions between bases -1438 to -909 and
-156 to -49. In summary, the proximal region of the
icIL-1Ra promoter, between bases -156 and -49,
contains positive cis-acting elements that are required
for expression in both epithelial cell and monocytic
cell lines.
Cells and tissues that express
the gene
sIL-1Ra is an inducible gene in most cells with maybe
the exception of astrocytes (Liu et al., 1998), whereas
icIL-1Ra is expressed constitutively in keratinocytes
and intestinal epithelial cells (for review see Arend
et al., 1998). Furthermore, icIL-1RaI mRNA is constitutively expressed in the epithelial cell lines A431
and HT29, but not in the macrophage cell lines RAW
264.7 and U937, or in the lymphocyte cell lines Raji
and Jurkat. However, icIL-1Ra mRNA expression
was induced in response to stimulation with LPS in
RAW 264.7 cells and to PMA and LPS in U937 cells
(Jenkins et al., 1997).
In normal mice and those injected with LPS, icIL1Ra mRNA was found only in the skin, whereas sIL1Ra mRNA was not detected in any tissues of normal
mice but was upregulated in spleen, lung, and liver of
LPS-treated mice (Gabay et al., 1997a). In normal
rabbits, IL-1Ra was constitutively produced in all
tissues examined (Apostolopoulos et al., 1996;
Matsukawa et al., 1997). All tissues produced sIL1Ra whereas thymus, cecum, skin, and kidney
produced both sIL-1Ra and icIL-1RaI.
Figure 2 The binding of IL-1Ra to IL-1R type I
does not trigger the formation of a trimolecular
complex, thus blocking signal transduction.
Residue 145 confers the agonistic (aspartic acid,
D) or the antagonistic (lysine, K) activity to the
Low affinity
bimolecular complex
High affinity
trimolecular complex
Accession numbers
Human: p18510
Rabbit: p26890
Mouse: p25085
Rat: p25086
cDNA sequences for bovine and horse IL-1Ra have
been described recently (Kato et al., 1997; Kirisawa
et al., 1998; Howard et al., 1998) but are not yet
accessible in data banks.
Human sIL-1Ra precursor is a 177 amino acid
glycoprotein comprising a signal sequence (amino
acids 1±25), a disulfide bound between Cys69 and
Cys116 (Schreuder et al., 1995), a potential Nglycosylation site at Gln109 and a cis-Pro at position
53. Human 18 kDa icIL-1Ra displays a sequence
similar to pro-sIL-1Ra with the N-terminal sequence
giving rise to a 159 amino acid unglycosylated protein
(Haskill et al., 1991). Rabbit, rat, mouse, bovine, and
horse sIL-1Ra predicted amino acid sequences display
around 75% sequence homology with human sIL1Ra, the rat and mouse sIL-1Ra precursor exhibiting
a signal sequence of 26 residues, being one amino acid
longer than that of human and rabbit sIL-1Ra. The
three forms of IL-1Ra found in humans, i.e. sIL-1Ra,
icIL-1RaI, and icIL-1RaII, were also identified in
mouse and rabbit (Goto et al., 1992; Cominelli et al.,
1994; Zahedi et al., 1994; Gabay et al., 1997a;
Matsukawa et al., 1997).
Description of protein
IL-1Ra displays a hydrophobic core and the typical
-trefoil structure with 12 strands which is found in
the IL-1 family of proteins (Stockman et al., 1992,
1994; Vigers et al., 1994). Residues Trp16, Gln20,
Tyr34, Gln36, and Tyr147 are crucial for the binding
of sIL-1Ra to the receptor (Evans et al., 1995).
Residue 145 (Lys in sIL-1Ra, Asp in IL-1) is crucial
in determining agonist or antagonist activity (Ju et al.,
1991). However, this region does not interact directly
with the receptor, either in IL-1Ra or in IL-1
(Schreuder et al., 1997), suggesting that this residue
might be important for the interaction with the IL-1
receptor accessory protein (IL-1R AcP) (Arend et al.,
1990; Schreuder et al., 1997) (Figure 2).
Discussion of crystal structure
The 3D structure of IL-1Ra has been determined by
X-ray crystallography and in solution by NMR
spectroscopy (Stockman et al., 1992, 1994; Vigers
et al., 1994; Schreuder et al., 1995, 1997). IL-1Ra has
12 strands connected by loops. Six of the strands
form a barrel structure that is closed at one end by the
324 Danielle Burger and Jean-Michel Dayer
remaining sheet. The overall structure of IL-1Ra is
similar to that of IL-1 and IL-1. Differences in
the amino acid sequence of the two types of protein
account for the interactions with the receptor,
triggering or not signal transduction through the
formation of the trimolecular complex IL-1/IL-1RI/
IL-1R AcP.
Important homologies
Recombinant human sIL-1Ra binds to mouse,
bovine, and rabbit IL-1 receptor with similar avidity.
This suggests that IL-1Ra has been well conserved
through evolution. Indeed, the amino acid sequences
of all the mammal IL-1Ra described to date display
> 75% homology, e.g. the deduced amino acid
sequence of bovine IL-1Ra demonstrated 80%,
78%, 78%, 77%, and 76% homology with human,
mouse, rat, rabbit, and horse sequences, respectively
(Kirisawa et al., 1998). There is poor sequence
homology between IL-1Ra and IL-1 or IL-1,
although all three proteins are derived from a unique
primordial precursor gene which gave rise to a
common IL-1/IL-1 gene and the IL-1Ra gene after
a gene duplication event which occurred some
350 million years ago (Eisenberg et al., 1991).
Posttranslational modifications
The only posttranslational event which occurs in sIL1Ra is glycosylation. Indeed, a potential N-glycosylation site is present in the IL-1Ra sequence of all
species described to date. However, the presence of
the oligosaccharide moiety does not seem to affect the
inhibitory activity of sIL-1Ra since both natural,
glycosylated sIL-1Ra and recombinant, unglycosylated sIL-1Ra display similar avidity to bind to the
IL-1 receptor. Therefore, glycosylation might protect
sIL-1Ra from proteolytic degradation and thus
prolong its lifespan in the extracellular space. Since
the intracellular forms of IL-1Ra are not translated in
the endoplasmic reticulum and are consequently not
processed through the Golgi, icIL-1RaI and icIL1RaII are not glycosylated.
Cellular sources that produce
It is very likely that all cell types able to produce
IL-1 and/or IL-1 will also express sIL-1Ra or
icIL-1Ra or both forms. However, by far the majority
of the studies have focused on the expression of sIL1Ra in monocyte-macrophages, neutrophils, and
fibroblasts and of icIL-1Ra in epithelial cells. The
induction of IL-1Ra production in various cells has
been extensively reviewed (Lennard, 1995; Dinarello,
1996; Arend et al., 1998). The differential expression
of IL-1 and IL-1Ra in different cell types of the
central nervous system has recently been described.
IL-1Ra (protein and mRNA) is constitutively
expressed in neurons of the paraventricular nucleus
and supraoptic nucleus. After administration of
endotoxin in rats, no additional cell expressed
immunoreactive IL-1Ra whereas IL-1 and IL-1
were induced in the same cell types, i.e. macrophages
in meninges and choroid plexus and microglial cells in
various brain regions. This suggests that in the brain
IL-1Ra is constitutively expressed by cell types other
than those expressing IL-1 (van Dam et al., 1998).
Eliciting and inhibitory stimuli,
including exogenous and
endogenous modulators
The production of IL-1Ra, and particularly that of
sIL-1Ra, has been extensively studied. Indeed, since
sIL-1Ra is usually produced by the same cell as IL-1,
the identification of factors able to modulate
differentially these productions has remained a
challenge. LPS induces both IL-1 and IL-1Ra in
monocytes. However, the expression kinetics of the
two proteins are different, the production of IL-1
and sIL-1Ra reaching its peak at 2 hours and 4 hours,
respectively (Vannier et al., 1992). Similarly, differential production of IL-1 and sIL-1Ra was observed
in vivo. LPS administered to human volunteers
induced the production of IL-1 and sIL-1Ra which
peaked 1 hours and 2 hours after injection,
respectively. Furthermore, peak plasma concentrations of IL-1Ra were about 100-fold higher than
those of IL-1 (Granowitz et al., 1991). In vitro, the
most potent inducer of IL-1Ra in monocytes is
adherent IgG which weakly induces IL-1 production. In monocytes activated by adherent IgG, high
concentrations of LPS reduce the expression of sIL1Ra but not that of IL-1. Together, these studies
indicate that different signaling pathways are involved
in the induction of IL-1 and IL-1Ra production.
Another important inducer of sIL-1Ra in monocytes
is direct cellular contact with stimulated T cells
(Burger and Dayer, 1998) which also concomitantly
induces the production of IL-1 and sIL-1Ra. In the
latter system, IL-1 and sIL-1Ra production is
controlled by different intracellular mechanisms
involving the differential effect of serine/threonine
phosphatases (Vey et al., 1997), the latter enzymes
having a positive effect on the induction of sIL-1Ra
and a negative one on the induction of IL-1. This
has been confirmed in a study demonstrating that
Raf-1 kinase, a serine/threonine kinase, is involved in
one of the pathways leading to sIL-1Ra production.
Interestingly, the Raf-1 and LPS pathways are
mutually antagonistic (Guthridge et al., 1997). The
ability of stimulated T lymphocytes to induce IL-1
and IL-1Ra is differentially modulated by drugs such
as leflunomide (DeÂage et al., 1998). IL-3 induces sIL1Ra production in monocytes to levels equivalent to
those induced by GM-CSF and LPS, whereas IL-1
and IL-4 are weak inducers (Jenkins and Arend,
Macrophages differentiated either in vivo (lung
alveolar macrophages, synoviocytes) or in vitro (GMCSF-treated monocytes) spontaneously produce large
amounts of sIL-1Ra (Roux-Lombard, 1998). This
production is increased by GM-CSF and IL-4
whereas LPS remains ineffective. Furthermore,
C-reactive protein (CRP) triggers the production of
IL-1 and sIL-1Ra in peripheral blood monocytes but
inhibits it in alveolar macrophages (Tilg et al., 1993;
Pue et al., 1996).
In polymorphonuclear neutrophils (PMNs), sIL1Ra, but not icIL-1Ra, is mainly induced by LPS,
GM-CSF, and TNF (Malyak et al., 1994).
Interestingly, TNF is a poor inducer of sIL-1Ra in
monocytes. The induction of sIL-1Ra in PMNs is
synergistically enhanced by IL-4 and IL-10, but not
by IL-13 and TGF. IFN increases the release of
sIL-1Ra in LPS- and fMLP-stimulated PMNs
(McDonald et al., 1998).
In human microglia, IFN induces IL-1Ra
production and enhances LPS- and IL-4-induced
IL-1Ra production, whereas it suppresses LPS- and
IL-1-induced IL-1 production. In contrast, IFN
inhibits both IL-1- and IL-1Ra-induced production
(Liu et al., 1998). sIL-1Ra and IL-1 production by
PMNs is also differentially induced by microcrystals,
favoring that of IL-1 (Roberge et al., 1994).
The potent induction of sIL-1Ra by either LPS or
GM-CSF might be modulated by other cytokines
such as IL-4, IL-10, and IL-13 which potentiate sIL1Ra production and simultaneously inhibit IL-1
production (Jenkins and Arend, 1993; Jenkins et al.,
1994). Interestingly, although exogenous IL-1 is a
poor sIL-1Ra inducer in monocytes, the induction of
endogenous IL-1 by TGF in monocytes is required
for the triggering of sIL-1Ra production (Wahl et al.,
1993). Activin A, a member of the TGF family, has
been shown to regulate the production of IL-1Ra and
IL-1 in monocytic cells. Activin A inhibits the
production of IL-1 and enhances that of IL-1Ra in
activated THP1 and U937 human monocytic cells. It
is noteworthy that activin A regulates cytokine
production at a posttranscriptional level (Ohguchi et
al., 1998). IFN also differentially modulates IL-1Ra
and IL-1 production in PHA-stimulated peripheral
blood mononuclear cells (PBMCs) by inhibiting the
production of IL-1 and enhancing that of IL-1Ra
(Coclet-Ninin et al., 1997). Retinoic acid differentially
regulates IL-1 and IL-1Ra production by alveolar
macrophages (Hashimoto et al., 1998).
IL-1Ra secreted form interacts with both IL-1
receptors. Natural and recombinant (unglycosylated)
sIL-1Ra display similar affinity for the mouse IL-1
receptor I to that of human IL-1 and IL-1
(dissociation constant  200 nM) (Seckinger et al.,
1987; Hannum et al., 1990; Eisenberg et al., 1990).
sIL-1Ra binding to IL-1 receptor I does not induce
signaling because it does not engage IL-1R AcP
(Cullinan et al., 1998). However, in addition to sIL1Ra, the biological activity of IL-1 is counterbalanced
by IL-1 soluble receptors (IL-1sR) which bind IL-1
and diminish the free concentration of soluble
cytokine, thus hampering its binding to the cell
surface receptor. Since IL-1sR can also bind IL-1Ra,
the two types of inhibitors might abolish their
respective inhibitory activity. Interestingly, the inhibitory effect of human sIL-1Ra is enhanced by type II
IL-1sR and hindered by type I IL-1sR (Burger et al.,
Recombinant human sIL-1Ra, icIL-1RaI, and
icIL-1RaII display similar affinity constants for type
II IL-1sR (2.9±3.8 107 Mÿ1 ), whereas icIL-1RaII
binds type I IL-1sR with a 4- to 5-fold lower affinity
constant (3.0 109 Mÿ1 ) than sIL-1Ra and icIL-1RaI
(1.2 and 1.4 1010 Mÿ1 ) (Malyak et al., 1998). In spite
of very similar affinity constants for IL-1 receptor
type I, large molar excess (10- to 100-fold) of sIL-1Ra
is required to efficiently inhibit IL-1 activity in vitro
(Arend et al., 1990). Similarly, preinjection of 100to 1000-fold molar excess of sIL-1Ra is required to
block systemic responses to IL-1 in animals (Fischer
et al., 1991).
In vitro, sIL-1Ra has mainly been used as a specific
inhibitor of IL-1 and IL-1 activity, since it is a
cytokine whose only known action is the competitive
inhibition of the binding of IL-1 to its receptor.
326 Danielle Burger and Jean-Michel Dayer
In vitro findings
IL-1Ra has been shown to inhibit all described IL-1
activities due to the binding of the agonist to its
receptor, although the concentration required to
abolish IL-1 effects is usually a 10- to 100-fold molar
excess of IL-1Ra over IL-1. More studies are
required to define the functions of intracellular forms
of IL-1Ra.
Regulatory molecules: Inhibitors
and enhancers
Since it does not induce signal transduction, the
`activity' of sIL-1Ra is regulated only by its levels of
production which are controlled by the above
mentioned inducers, inhibitors, and enhancers.
Normal physiological roles
In addition to the constitutive expression of icIL-1Ra
in epithelial cells and keratinocytes, sIL-1Ra seems to
be expressed at low levels in normal human subjects
and animals, despite some species-dependent differences. However, the function of IL-1Ra in normal,
i.e. `noninflammatory' conditions, remains elusive. It
has been postulated that tissue IL-1Ra is involved in
health maintenance by masking coexisting IL-1
activity in tissues (Matsukawa et al., 1997). In
healthy rabbits, sIL-1Ra is produced constitutively
in most tissues (lung, liver, spleen, thymus, cecum,
skin, kidney, heart, and brain), while thymus, cecum,
skin, and kidney produced both sIL-1Ra and icIL1Ra. In contrast, IL-1 activity has not been detected
in any tissues with the exception of skin and heart,
but became detectable after preincubation of the
samples with neutralizing antibodies to IL-1Ra,
demonstrating that constitutive but low expression
of sIL-1Ra inhibits IL-1 activity in physiological
conditions. On the other hand, studies on chick
embryo fibroblasts have shown that the balance
between the secreted cytokine network and IL-1Ra
levels may represent a homeostatic mechanism aimed
at controlling normal embryogenesis (Bodo et al.,
The physiological roles of endogenously produced
IL-1Ra have been investigated in mice that either lack
IL-1Ra or overproduce it under the control of the
endogenous promoter.
Knockout mouse phenotypes
Mice lacking IL-1Ra are more susceptible than
controls to lethal endotoxemia but less susceptible to
listeriosis (Hirsch et al., 1996). Furthermore, IL-1Ra
knockout mice had a significantly earlier onset of
collagen-induced arthritis, with increased severity (Ma
et al., 1998). This confirms the important role of IL1Ra in the regulation of IL-1 activity during infection
and inflammation. More intriguing is the fact that
IL-1Ra knockout mice have decreased body mass
compared with wild-type controls or IL-1 knockout
mice due to growth retardation after weaning (Hirsch
et al., 1996; Horai et al., 1998). This implies that
IL-1Ra plays an important but still elusive part in
normal physiology.
Transgenic overexpression
The effect of IL-1Ra overexpression has been assessed
in several animal models of disease in which IL-1 was
claimed to be involved. Mice overexpressing the IL1Ra gene under the control of its endogenous
promoter had a significant reduction in both
incidence and severity of collagen-induced arthritis
suggesting that the endogenous expression of IL-1Ra
is a critical determinant of susceptibility to the disease
(Ma et al., 1998). Interestingly, after immunization
with type II collagen, IL-1Ra mRNA was overexpressed in the spleens, but not in the injection paws,
of transgenic mice (Ma et al., 1998). On the other
hand, IL-1Ra overproducers are protected from the
lethal effects of endotoxin while being more
susceptible to listeriosis. Following an endotoxin
challenge serum levels of IL-1 are decreased in
IL-1Ra-null mice and increased in IL-1Ra overproducers in comparison to controls (Hirsch et al., 1996).
Transgenic mice with distal airway epithelial cell
expression of human IL-1Ra were partially protected
from IL-1-induced airway inflammation and injury
(Wilmott et al., 1998).
Pharmacological effects
Since IL-1Ra is able to counteract the proinflammatory effects of IL-1, recombinant sIL-1Ra has been
used as therapeutic agent in many animal disease
models. These models were recently reviewed (Arend
et al., 1998) and covered mainly infectious and
inflammatory diseases. Exogenous IL-1Ra, usually
administered intravenously, led to at least partial
prevention or treatment of disease. However, the
necessity of systemic IL-1Ra injections in large
amounts limits the application of this therapy in
human patients. New approaches have recently been
tested applying exogenous IL-1Ra directly at the
inflammatory site. These gene therapy trials were
mainly carried out in animal models of rheumatoid
arthritis and osteoarthritis using either adenoviral
gene transfer into the joint or ex vivo gene transfer in
synoviocytes and autograft (Arend et al., 1998).
Interestingly, endogenously produced IL-1Ra was
mainly chondroprotective, displaying only weak antiinflammatory properties. Therefore, IL-1Ra gene
therapy displays some efficacy in inflamed animal
joints mainly by diminishing cartilage destruction.
Few trials have been carried out in other systems,
although the transfer of IL-1Ra gene into neuronal
cells, hematopoietic stem cells and lungs has been
successful (Davidson et al., 1993; Boggs et al., 1995;
McCoy et al., 1995). IL-1Ra overexpression in mouse
brain by adenoviral vector attenuates the activation
of inflammatory cells during focal cerebral ischemia
( Yang et al., 1998). IL-1Ra may also be upregulated
in rat brain by peripheral administration of kainic
acid (Eriksson et al., 1998).
Interactions with cytokine network
IL-1 being a potent inducer of many other cytokines,
the inhibition of its effects by IL-1Ra clearly has an
important impact on the cytokine network. Furthermore, since IL-1 may induce the production of its
inhibitor, sIL-1Ra might regulate its own production
in some circumstances.
Endogenous inhibitors and
IL-1Ra is usually produced by the same cells which
produce IL-1 and/or IL-1. Besides, similar stimuli
induce the production of both agonist and antagonist
cytokines. Therefore, many studies have been devoted
to the study of factors affecting the balance between
IL-1Ra and IL-1 production, i.e. IL-4, IL-13, and IL10 favoring the production of sIL-1Ra over that of
IL-1. Interestingly, both TH1 and TH2 cytokines,
i.e. IFN and IL-4, antagonize the inhibition of
sIL-1Ra production by LPS-stimulated monocytes
in the presence of glucocorticoids (Parsons et al.,
1997), although IFN but not IL-4 acts through an
IL-1-dependent mechanism. Therefore, coinfusion of
glucocorticoids and cytokine should favor the production of IL-1Ra over that of IL-1.
The role of IL-1Ra in normal physiology of healthy
humans remains elusive. Only animal models have
shed light on the possible role of IL-1Ra in normal
biological processes. Indeed, in contrast with IL-1
knockout mice, IL-1Ra knockout mice display
growth retardation, suggesting an important role for
IL-1Ra in normal physiology where it could mask
coexisting IL-1 activity in tissues. However, additional studies are required to clarify the roles of
IL-1Ra isoforms in normal biologic processes particularly in humans. Because sIL-1Ra levels are elevated
in the peripheral blood of patients with various
diseases, it has recently been suggested that IL-1Ra is
an acute phase protein (Gabay et al., 1997b).
Furthermore, the use of neutralizing antibodies has
demonstrated the importance of IL-1Ra as a natural
anti-inflammatory protein in animal models of
diseases. In analogy a similar role for IL-1Ra has
been suggested in humans. Indeed, as recently
reviewed (Arend et al., 1998), extensive evidence
indicates that IL-1Ra is produced by many tissues in
healthy humans and that its production is upregulated in the host response to infection and acute and
chronic inflammation.
Normal levels and effects
Except for allele 2 carriers, low levels of circulating
sIL-1Ra have been detected in healthy humans (400±
800 pg/mL) which were drastically increased in
various pathological conditions (Table 2). The
increase in IL-1Ra level in such diseases does not
seem to counteract efficiently the inflammatory effects
of IL-1. However, studies using neutralizing anti-IL1Ra antibodies in animal models of disease indicate
an anti-inflammatory effect of endogenous IL-1Ra.
On the other hand, the levels of IL-1Ra were found to
be locally enhanced in acute and chronic disorders
such as rheumatoid arthritis (Firestein et al., 1992;
Malyak et al., 1993), osteoarthritis, and Lyme arthritis
(Miller et al., 1993), and nonperforating Crohn's
disease (Gilberts et al., 1994).
328 Danielle Burger and Jean-Michel Dayer
Table 2 Diseases with increased circulating IL-1Ra level
Chronic arthritis
Jouvenne et al. (1998)
Insulin-dependent diabetes mellitus
Netea et al. (1997)
Systemic lupus erythematosus
Sturfelt et al. (1997)
Gynecological cancers
Fujiwaki et al. (1997)
Pediatric sepsis syndrome
Samson et al. (1997)
Kimya et al. (1997)
Acute myocardial infarction
Shibata et al. (1997)
Graft-versus-host disease
Schwaighofer et al. (1997)
Hemophagocytic lymphohistiocytosis
Henter et al. (1996)
Patients with burns
Endo et al. (1996)
Bronchial asthma
Yoshida et al. (1996)
Chronic renal failure
Deschamps-Latscha et al. (1995)
Systemic chronic juvenile arthritis
De Benedetti et al. (1995)
Gabay et al. (1994)
Septic shock
Rogy et al. (1994)
Role in experiments of nature
and disease states
The serum levels of sIL-1Ra are elevated in many
pathologies. However, only few studies contemplate
the determination of IL-1Ra as a diagnostic test. In
inflammatory bowel disease the balance between IL-1
and sIL-1Ra might influence disease expression. It
was demonstrated that patients with active Crohn's
disease had significantly higher serum sIL-1Ra levels
than patients with active ulcerative colitis. Therefore,
levels of sIL-1Ra in the peripheral blood of patients
with inflammatory bowel disease are of clinical
relevance, representing a marker of disease activity
and a possible differential diagnostic marker (Propst
et al., 1995). More recently, it has been shown that
serum levels of sIL-1Ra and IL-6 were enhanced
2 days before the clinical manifestation of neonatal
sepsis (Kuster et al., 1998). While circulating sIL-1Ra
levels are increased in patients at risk for acute
respiratory distress syndrome (ARDS) who die, it does
not predict the development of the syndrome
(Parsons et al., 1997). Furthermore, it was recently
suggested that in chronic polyarthritis elevated levels
of IL-1Ra may reflect increased production and
activity of IL-1, in contrast with the levels of
endogenous type II IL-1sR which may constitute a
natural anti-inflammatory factor. This should be
taken into account when considering these molecules
as prognostic markers or for therapeutical usage
(Jouvenne et al., 1998). In renal transplant recipients,
patients with high IL-1Ra/IL-1 ratios in urine are
less prone to acute allograft rejection than patients
with low IL-1Ra/IL-1 ratios (Teppo et al., 1998).
Rejection episodes in orthotopic heart transplantation are accompanied by a renewed and more
pronounced elevation in IL-1Ra (serum levels beyond
4000 pg/mL) for at least 2 days, indicating that IL1Ra might have a predictive value in the detection
of acute allograft rejection (Thiele et al., 1998).
Preclinical ± How does it affect
disease models in animals?
As stated above, the therapeutic use of sIL-1Ra has
been tested in many animal models of diseases
(Table 3). This has been extensively reviewed (Arend
et al., 1998). Some studies published in 1998 have
shown that IL-1Ra was also efficient in the treatment
of experimental allergic encephalomyelitis (EAE ), the
animal model for multiple sclerosis (Badovinac et al.,
1998), although IL-1Ra was administered before
disease onset. Indeed, dark Agouti rats which were
treated during the induction phase of EAE (days 0±6)
with IL-1Ra (350 g/rat/day) developed milder
Table 3 Animal models of diseases improved by IL-1Ra administration
Model of disease
Acetic acid-induced colitis
Allergen-induced late asthmatic reaction
Guinea pigs
Allosensitization in corneal transplantation
Antigen-induced airway hyperreactivity
Guinea pigs
Antigen-induced arthritis
Antiglomerular basement membrane antibody-induced glomerulonephritis
Apolipoprotein E-deficient mice
Bacterial meningitis
Bleomycin- and silica-induced pulmonary fibrosis
Cardiac allograft immunoreactivity
Carrageenan-induced pleurisy
Cerulein-induced experimental acute pancreatitis
Collagen-induced arthritis
Crescentic glomerulonephritis
Cyclophosphamide-induced myelotoxicity
Diabetes recurrence after syngeneic pancreatic islet transplantation
Dimethylnitrosamine-induced hepatic fibrosis
Dinitrofluorobenzene-induced contact hypersensitivity
Endotoxin-induced mastitis
Endotoxin-induced uveitis
Rats, rabbits
Experimental allergic encephalomyelitis
Experimental heatstroke
Experimental shigellosis
Graft-versus-host disease
Immune complex-induced arthritis
Immune complex-induced colitis
Immune complex-induced lung injury
Intestinal anaphylaxis
Guinea pigs
Ischemia/reperfusion lung injury
Ischemic brain injury
Mice, rats
Islet allograft rejection
KMnO4-induced granuloma
LPS-induced pleurisy
Monocrotaline-induced pulmonary hypertension
Oleic acid-induced lung injury
Osteoclast formation and bone resorption in ovarectomized animals
Mice, rats
Oxidant-induced arthritis
Postcardiac transplant coronary arteriopathy
Preterm delivery induced by IL-1
Septic shock
Mice, rats, rabbits, baboons
330 Danielle Burger and Jean-Michel Dayer
Table 3 (Continued)
Model of disease
Silver nitrate-induced secondary amyloidosis
Spontaneously occurring IgA nephropathy
Staphylococcal-induced arthritis
Streptococcal cell wall-induced arthritis
Streptococcal cell wall-induced colitis
Streptozotocin-induced diabetes
symptoms than control animals immunized with
encephalitogen. Furthermore, isolated lymph node
cells from myelin basic protein-primed rats which
were restimulated in vitro in the presence of IL-1Ra
(10 mg/mL) and transferred to naive syngeneic
animals display diminished encephalitogenic capacity.
This correlates with a lower proliferative response to
antigen and mitogen and decreased expression of IL-2
receptors in lymph node cells treated with IL-1Ra.
The beneficial effect of IL-1Ra in EAE is improved
by coinfusion of type I TNF soluble receptor in terms
of clinical severity, frequency of disease, loss of body
weight, and day of onset (Wiemann et al., 1998). In
the latter study, the treatment began at day 8 after
EAE induction by myelin basic protein, i.e. 3 days
prior to disease onset in untreated animals. Besides,
suppression of allosensitization by topical application
of IL-1Ra enhances corneal transplant survival
(Yamada et al., 1998).
Effects of therapy: Cytokine,
antibody to cytokine inhibitors, etc.
The beneficial effects of IL-1Ra as a therapeutic agent
have been demonstrated in many animal models of
diseases, although infused doses of IL-1Ra were
usually very high. Despite the fact that humans are
the most sensitive species to IL-1, i.e. 1 ng/kg of intravenous IL-1 in healthy volunteers induced symptoms (Dinarello, 1996), and that coinfusion of IL-1Ra
and endotoxin did not reduce endotoxin-induced
symptoms, fever, and tachycardia (Granowitz et al.,
1993), IL-1Ra was used in clinical trials in patients
with sepsis. In contrast with animal models, IL-1Ra
was inefficient in enhancing the survival of sepsis
patients (Arend et al., 1998).
On the other hand, IL-1Ra might mediate the
effects of other cytokines used as therapeutic agents.
Indeed, IL-1Ra is elevated in healthy volunteers
who received a single dose of IFN-2b (Reznikov
et al., 1998) confirming previous observations in
IFN-treated patients with chronic hepatitis C
(Naveau et al., 1997).
Intravenously administered IL-1Ra displays a short
lifespan in human, exhibiting an initial half-life of 21
minutes and a terminal half-life of 108 minutes
(Granowitz et al., 1992). This might explain the
limited action of IL-1Ra in therapy (Arend et al.,
1998). Although this was considered a positive feature
in treating acute diseases, IL-1Ra was revealed to be
inefficient in the treatment of sepsis. This short halflife IL-1Ra was also used in clinical trials for the
treatment of chronic diseases such as rheumatoid
arthritis and graft-versus-host disease (Campion et al.,
1996; Antin et al., 1994; Bresnihan and Cunnane,
1998). A recent study has shown that administration
of IL-1Ra in a slow-release vehicle such as hylan fluid
improves pharmacokinetics and efficacy in rat type II
collagen arthritis (Bendele et al., 1998). Indeed, in
female Lewis rats with established type II collagen
arthritis, subcutaneous injection of single daily doses
of IL-1Ra (100 mg/kg) in hylan fluid results in a
slower release of IL-1Ra in the bloodstream and maintains therapeutic blood levels of IL-1Ra (1 mg/mL) for
a longer period than does IL-1Ra in citrate-buffered
saline with EDTA and polysorbate. Animals treated
with single daily dose of IL-1Ra in hylan fluid
displayed 78% inhibition of paw swelling over time
whereas similar doses of IL-1Ra in the other vehicle
were unefficient.
IL-1Ra does not display toxicity. Indeed, the
intravenous infusion of 10 mg/kg of IL-1Ra in
healthy human volunteers, i.e. a 10 million-fold
molar excess, is without effect (Dinarello, 1996).
Healthy volunteers who for 3 hours had received a
continuous intravenous infusion of IL-1Ra doses
ranging between 1 mg/kg and 10 mg/kg displayed no
significant clinical difference as compared with salineinfused individuals in terms of symptoms, physical
examinations, complete blood counts, mononuclear
cell phenotypes, blood chemistry profiles, and serum
iron and serum cortisol levels. The main difference
was that PBMCs obtained after completion of the IL1Ra infusion synthesized less IL-6 ex vivo than
PBMCs from saline-injected controls. This suggests that the transient blockade of IL-1 receptors is
safe and does not significantly affect homeostasis
(Granowitz et al., 1992).
Clinical results
Although IL-1Ra was inefficient in sepsis treatment,
clinical trials are currently undertaken in inflammatory diseases. The results of one of these trials
enrolling 472 patients with rheumatoid arthritis were
recently published (Bresnihan et al., 1998). They
demonstrate that sIL-1Ra is the first biologic agent
displaying a beneficial effect on the rate of joint
erosion. Treatment with sIL-1Ra was evaluated in
four groups of patients who received placebo or a
single, self-administered subcutaneous injection of
sIL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg.
IL-1Ra was well tolerated and no serious adverse
effects were observed, an injection-site reaction being
the adverse event most frequently observed. At
24 weeks, the rate of radiologic progression in the
patients receiving sIL-1Ra was significantly less than
in the placebo group. Of the patients who received
150 mg/day of sIL-1Ra, 43% met the American
College of Rheumatology criteria for response (the
primary efficacy measure), 44% met the Paulus
criteria, and statistically significant improvements
were seen in the number of swollen joints, number of
tender joints, investigator's assessment of disease
activity, patient's assessment of disease activity, pain
score on a visual analog scale, duration of morning
stiffness, Health Assessment Questionnaire score, Creactive protein level, and erythrocyte sedimentation
rate. This study confirmed both the efficacy and the
safety of IL-1Ra in a large cohort of patients with
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Recombinant sIL-1Ra is commercialized under the
name of Antril (Synergen/Amgen).
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