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Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1
, which are evolutionarily related (1).
Both IL-1 and IL-1 are synthesized as 31-kDa precursors that lack
signal peptides. The mature agonists are 17-kDa proteins that elicit
virtually identical biological responses. During signaling, IL-1 binds
first to the type I receptor
(IL-1RI3 or p80), and
this complex then recruits the IL-1R accessory protein, a homologue of
IL-1RI. Formation of the ternary IL-1 signaling receptor complex leads
to high affinity binding and signal transduction (2). The
third member of the IL-1 family of ligands is the IL-1R antagonist
(IL-1ra) (reviewed in Ref. 3). It binds to the same
receptors as the agonists, but does not elicit any detectable
biological response, since the binary complex formed by IL-1ra bound to
IL-1RI fails to recruit the IL-1R accessory protein and thus fails to
transduce a signal (2).
A single gene encodes all isoforms of IL-1ra (Fig. 1
A). One is a secreted protein
(sIL-1ra) of 17 kDa that has a canonical signal peptide. It is
synthesized as a 20-kDa precursor, processed, and released from cells
via the classical secretory pathway. The other isoforms of IL-1ra are
intracellular; they lack a functional leader sequence and remain in the
cytosol. The 18-kDa intracellular IL-1ra (icIL-1ra1) isoform arises via
alternative splicing that removes the signal peptide. Intracellular
IL-1ra2 contains an additional in-frame exon and has only been
described in humans (4, 5). The 16-kDa icIL-1ra3 isoform
arises by translational initiation at an internal methionine codon
within the sequence common to all IL-1ra mRNAs (6, 7, 8).
Intracellular IL-1ra3 is unique in that it binds to IL-1Rs 
5-fold
less avidly than do the other IL-1ra isoforms and presumably functions
less efficiently as a receptor antagonist of IL-1 (7).
While sIL-1ra has been well studied, the functions of the intracellular
variants remain unknown. One study proposes that icIL-1ra1 may function
intracellularly to reduce the half-life of IL-1-induced mRNAs
(9). Intracellular IL-1ra1 may have a unique role in
resolving the inflammation of synovial tissues during collagen-induced
arthritis (10). The relative contributions of the
different IL-1ra isoforms to the in vivo regulation of inflammatory and
immune responses remain largely unresolved. We undertook an analysis of
IL-1ra mutant mice, including epistasis/genetic rescue experiments, to
investigate the contributions of the different isoforms to various
experimental paradigms.
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Epistasis is a genetic method used to study the interaction between two or more genes that control a single phenotype. Animals with mutations in each gene are mated, and the phenotypes of the offspring are analyzed. If one mutant gene masks the phenotype of a second mutant gene, then the first gene is considered to be epistatic to the second. Epistasis tests reveal whether the two gene products function in the same or parallel pathways and can further establish the hierarchical relationship, if any, that exists between them. We employed these methods to investigate the interrelationships between the IL-1RI and the different isoforms of IL-1ra using genetically manipulated strains of mice that lack all isoforms of IL-1ra (rako), mice that overexpress the mRNA for sIL-1ra only (ratg), and mice that lack the IL-1RI (RIko). We found that the deletion of IL-1RI as well as overexpression of the mRNA of sIL-1ra via a transgene are epistatic to deletion of all IL-1ra isoforms. Therefore, the sIL-1ra mRNA splice variant, which encodes both sIL-1ra and icIL-1ra3 isoforms, is sufficient to regulate all aspects of IL-1ra biology investigated. The roles of the intracellular splice variants remain unknown. Our results also show that the functions of IL-1ra in development, inflammation, and infection are dependent upon the presence of a functional IL-1RI; there is no other receptor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As described in detail previously (11, 12), the
single-mutant mouse strains used in these experiments are mice that
lack IL-1RI (RIko), mice that lack all forms of IL-1ra
(rako), and mice that hemizygously carry a transgene that
encodes the sIL-1ra mRNA under control of its endogenous promoter
(ratg). The ratg line used for these experiments
has been previously referred to as T14. Double mutants were generated
by crossing the single-mutant strains to create founders for the
various strains. Briefly, the following matings were used to generate
mice for experiments: RIko from -/- x -/- or +/- x
-/- or +/- x +/-; rako from +/- x +/- (because -/-
are infertile; see below); ratg from T14/o x +/+;
rako, RIko from +/-, +/- x +/-, +/- or -/-, -/- x
-/-, -/- or -/-, -/- x +/-, -/- or -/-, -/- x -/-,
+/-; rako, ratg from -/-, T14/o x +/-, o/o; and
ratg, RIko from T14/o, +/- x o/o, -/-. Wild-type
(wt) controls were either littermates of ratg
hemizygotes, littermates of rako mice, or occasionally the
offspring of wt sibling matings. Genotyping was performed by
PCR as previously described (11). All mice used in these
experiments were backcrossed to C57BL/6J genetic backgrounds for 
10
generations, bred in a specific-pathogen-free facility, and handled in
accordance with institutional guidelines.
Monitoring of development/homeostasis
For the monitoring of postnatal developmental abnormalities in the mutant mice, littermates were caged together (three or four mice per cage) and allowed access to food and water ad libitum. Once a week, from 3–52 wk of age, mice were weighed and scored for the presence of sickness symptoms by an investigator who was blinded to the genotypes of the mice (n = 14–36/genotype/sex). To judge sickness, a scale of 0–10 was used to access both the number and the severity of sickness symptoms (including lethargy, piloerection, hunched posture, etc.), with 0 being no abnormalities, and 10 being moribund/dead. Fertility was ascertained by mating mutant mice and littermate controls starting at 6–7 wk of age with proven breeders (n = 10/genotype/sex).
Models of septic shock and listeriosis
Endotoxic shock was induced as previously described using LPS from Salmonella typhimurium (Sigma, St. Louis MO) at 10 µg/g administered i.p. (11). For studying primary listeriosis, L. monocytogenes EGD was injected i.v. at a dose of 1.0 x 106 CFU in 100 µl. Bacteria were enumerated by homogenization of organs in sterile PBS and plating serial log dilutions (14). For both challenge experiments, age-matched mice were inoculated on the same day, and survival was monitored for a total of 7 days postchallenge (n = 5–15/genotype/sex). The results reported are cumulative from three to five repeat experiments.
Analysis of blood and serum
Serum collection and blood analysis were performed as previously
described (11, 14). ELISAs were performed as previously
described and followed the manufacturers’ suggested protocols using
the following Abs or kits: polyclonal goat anti-mIL-1ra (R&D
Systems, Minneapolis, MN); DuoSet kits for IL-1, IL-10, and TNF-
(R&D Systems); and OptEIA for IFN-
(BD PharMingen, San Diego,
CA).
Protein isolation and immunoblotting
For protein isolation, we used a modification of the TRIzol reagent protocol (Life Technologies, Gaithersburg, MD). Briefly, murine tissues were homogenized in TRIzol reagent. Following RNA isolation and removal of DNA, the proteins were isopropanol-precipitated, washed once in 0.3 M guanidine HCl/95% ethanol, and then resuspended in 6 M guanidine HCl. After dialysis overnight at 4°C with three changes of 10 mM Tris-HCl (pH 7.0) using Slide-A-Lyzer cassettes (10-kDa Mr cut-off; Pierce, Rockford, IL), the dialysate was collected and cleared by centrifugation (10,000 x g, 15 min, 4°C). The protein concentration of the resulting supernatant, which contained all the isoforms of IL-1ra (data not shown), was quantitated using the Bradford assay kit (Bio-Rad, Hercules, CA). For immunoblot analysis, 20 µg total protein was loaded on a 17.5% polyacrylamide gel and transferred to polyvinylidene difluoride membranes (Bio-Rad). Membranes were blocked for 1–2 h at room temperature in 10% nonfat dry milk in PBS/Tween, washed, incubated with 0.2 µg/ml biotinylated polyclonal goat anti-mouse IL-1ra Ab (R&D Systems) for 1 h at room temperature, washed again, and finally incubated with streptavidin-HRP (1/1,000 dilution; Amersham Pharmacia Biotech, Piscataway, NJ). Positive signal was visualized using ECL detection reagents (Amersham Pharmacia Biotech) following the manufacturer’s recommended protocol.
FACS analysis
Single-cell suspensions from thymi, spleens, and bone
marrows, pooled from femur and tibia, were isolated from mutant and
wt mice following standard protocols. After lysis of RBC,
106 cells were stained for 30 min with the
appropriate combination of mAbs. Cells were washed (3% FCS and 0.1%
sodium azide/PBS), stained with secondary reagents when necessary for
30 min, washed again, and analyzed with a FACSCalibur cytometer (BD
Biosciences, San Diego CA). The mAbs used for staining were
anti-CD45R/B220-PE (RA3-6B2), anti-CD3-FITC (17 A2),
anti-CD8a-PerCP (Ly-2/53-6.7), anti-CD4-FITC (L3T4/RM4-5),
anti-CD69-PE (H1.2F3), and anti-
TCR-biotin (GL3; all
from BD PharMingen), and anti-Mac-1-biotin (M1/70) and
anti-IgM-allophycocyanin (a gift from G. Siu). For the
biotin-conjugated mAbs, the secondary staining reagent used was
streptavidin-PE (BD PharMingen).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The rako mice lack all IL-1ra isoforms
(11). They show abnormal development, including postnatal
runting, reduced fertility, and early mortality from an unknown cause.
Individual variability exists as to age of onset, symptom progression,
and age of death. Nevertheless, certain generalizations can be made.
The first detectable symptom, at 5–6 wk of age, is postnatal runting
caused by failure to gain weight, primarily body fat (Fig. 2) (15). At the same time,
although otherwise asymptomatic, rako mice have an altered
cellular profile, including pronounced neutrophilia and mild
leukocytosis (Table I). At 8–10 wk of
age, rako mice have normal thymic cell populations, but
alterations in some splenic cell types, specifically an increase in
both T cells (2.15 vs 1.56% for rako vs
wt mice, respectively; n = 7
females/genotype; p = 0.03, by Student’s t
test) and Mac-1+ cells (16.5 vs 14.2%;
p = 0.02). Mac-1+ cells are also
increased in the bone marrow of rako mice (42.5 vs 28.4%;
n = 4 females/genotype; p = 0.02).
Similar altered cellular profiles are present in rako males.
Young adults are also subfertile; 50% of males and 30% of females
were able to reproduce compared with 90–100% of wt and
heterozygous littermates (n = 10/sex/genotype).
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We have taken a genetic epistasis approach to investigate the mechanism
of action of the lack of IL-1ra on development and homeostasis. We
constructed rako, RIko double mutants. RIko,
which is developmentally normal, is epistatic to rako;
deleting the type I receptor fully rescues the developmental phenotypes
of rako mice (Fig. 2
and Table I). Further, the
double-mutant IL-1ra-/-,
IL-1RI+/- displays a partially dominant
epistatic phenotype. As shown in Fig. 2, removing a single RI allele
restores rako halfway to wt weights, while
removal of both alleles (rako, RIko) completely restores
them. Removing a single RI allele also delays, rather than prevents,
the onset of infertility and sickness symptoms (age of 50% affliction:
females, 21 wk (n = 18); males, 27 wk
(n = 16)) and improves 1-yr survival (64% (9 of 14)
females and 92% (11 of 12) males; compare above). The single-mutant
IL-1RI+/- is phenotypically wt, and
there is no difference in phenotype of the
IL-1ra-/-, IL-1RI+/-
mutants that correlates with parental inheritance of wt or
knockout RI allele, i.e., no imprinting or other epigenetic inheritance
mechanism is suggested (data not shown). Taken together, these data
indicate that the developmental abnormalities seen in the
rako mice are dependent upon the presence as well as the
gene dosage of the IL-1RI.
The double-mutant rako, ratg was also generated by crossing
the two IL-1ra mutant strains. These rako, ratg doubles show
the same developmental phenotype as the ratg parental
strain, which is that of wt. Thus, ratg is
epistatic to rako. The developmental phenotype, including
runting, neutrophilia, fertility, and earlier mortality, can be rescued
by overexpression of the sIL-1ra splice variant mRNA (Fig. 2, Table I,
and data not shown).
To investigate more thoroughly which isoform of IL-1ra was responsible
for this complete dominant epistasis, we analyzed the IL-1ra protein
isoforms present in the various mutant mice. Both sIL-1ra and icIL-1ra3
isoforms were detected in the livers of all mice except
rako, while the icIL-1ra1 isoform was not present in
rako or rako, ratg mutants (Fig. 1). This
demonstrates that the sIL-1ra mRNA encoded by the transgene produces
both sIL-1ra and icIL-1ra3. Therefore, the genetic epistasis we
observed could be caused by either one or both of these isoforms. Our
results also show that the alternative splice variant, icIL-1ra1, does
not play an essential role in the developmental processes affected by
the deletion of IL-1ra.
Further, our results suggest that sIL-1ra mRNA, not icIL-1ra1 mRNA, is
the predominant source of icIL-1ra3 in vivo. Intracellular IL-1ra3 is
coexpressed with sIL-1ra in the liver following LPS administration, but
icIL-1ra3 is not coexpressed with icIL-1ra1 in the skin of unstimulated
mice (Fig. 1). After LPS administration, wt mice express all
isoforms of IL-1ra in the skin, while rako, ratg mice
express only sIL-1ra and icIL-1ra3 (data not shown). Therefore, either
icIL-1ra3 is expressed exclusively from sIL-1ra mRNA or the alternative
translation of all IL-1ra mRNAs is induced by systemic LPS
administration, which is required to induce the expression of
sIL-1ra. Tissue and stimulus-specific factors or the different upstream
mRNA sequences might regulate this differential expression. Similar
conclusions have recently been drawn regarding the expression of
icIL-1ra3 from studies of transgenic mice constitutively overproducing
human IL-1ra isoforms (16).
Responses to infectious and inflammatory challenges
As described in the introduction, the differences reported
for the phenotype of ratg vs that of RIko created
an apparent paradox that questioned whether IL-1ra functions
exclusively at the IL-1RI and whether IL-1 is essential for the host
response to infection and inflammation. To investigate this, we
backcrossed both ratg and RIko mutants to the
C57BL/6J strain for at least 10 generations and examined their
responses to models of infection and inflammation side-by-side, along
with wt littermate controls. In our hands, infection with
the intracellular pathogen, L. monocytogenes
(106 i.v., strain EGD) shows that both
ratg and RIko differ from wt in
survival and titers. Similarly, in a model of septic shock (i.p.
administration of 10 µg/g LPS from S. typhimurium) both
mutants were nearly identical in affording protection from lethality
compared with wt mice (Table II). Thus, on a C57BL/6J genetic
background, overexpressing IL-1ra has the same effect as removing
IL-1RI, supporting the view that IL-1 signaling is essential in
promoting clearance of bacterial infections but is detrimental to
survival after systemic inflammatory challenge.
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The results show that RIko is epistatic to rako;
the double mutant has the same survival rate as the RIko
mutant alone. The same is true for the rako, ratg double
mutant; the double mutant has the phenotype of the ratg
parent. Overall, these data indicate that the sIL-1ra splice variant
mRNA is sufficient to regulate inflammatory and infectious responses,
and that its function is dependent upon the presence of the type I
receptor. Finally, we constructed a ratg, RIko double-mutant
strain. It has survival rates nearly identical with each of the
parental strains that are themselves identical. Additive effects are
not seen in this double mutant, re-enforcing the conclusion that the
gene products encoded by the sIL-1ra transgene function only through
IL-1RI and that there is no other target for IL-1ra. Cytokine profile during septic shock
We previously reported parallel IL-1 and IL-1ra protein levels in serum following LPS administration, i.e., higher in the IL-1ra overexpressors and lower in the knockouts compared with wt mice (11). These in vivo results were counterintuitive, because earlier experiments had implicated IL-1 in an autoinduction, self-amplifying cascade (17, 18, 19, 20). We analyzed other cytokine profiles during sepsis in all single- and double-mutant strains to establish whether the parallel serum accumulation of IL-1 and IL-1ra is confined to the IL-1 system.
Sera were collected at 0, 1, 3, 8, and 16 h after administration
of 10 µg/g LPS and were analyzed by ELISA to determine the levels of
IL-1, IL-1ra, TNF-, IFN-, and IL-10. As presented in Table II,
the parallel regulation of IL-1 and IL-1ra was observed in all IL-1
system mutants, with peak levels of both cytokines elevated in the
RIko and ratg mutants, and both diminished in the
rako mutants, compared with wt controls. The
levels of TNF-, IFN-, and IL-10 were not different from those in
wt throughout the inflammatory response in any mutant strain
(data not shown). These results indicate that the parallel regulation
of serum cytokine levels is confined to the IL-1 family of ligands. The
analysis of the double mutants again shows that RIko and
ratg are epistatic to rako, indicating that the
observed phenotypes reflect the in vivo activity of the proteins made
by the sIL-1ra splice variant acting through the type I receptor.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell populations is
consistent with the known activities of IL-1 as a cofactor for the
proliferation and activation of both these cell types (1, 23, 24).
Eliminating the receptor (RIko) rescues rako
developmental phenotypes. This indicates that IL-1ra functions during
development depend upon the presence of the type I receptor. It further
demonstrates that the IL-1 system functions during normal development
and homeostasis and is sensitive to the gene dosage levels of IL-1RI
expression, because IL-1ra-/-,
IL-1RI+/- double mutants have intermediate
phenotypes. Our results also show that the rako
developmental phenotype can be suppressed by overexpression of the
sIL-1ra splice variant mRNA from a transgene. It should be noted that
all relevant controls, ratg, RIko,
IL-1ra+/-, and IL-1RI+/-
mutants, are phenotypically indistinguishable from wt mice
in development and adult homeostasis. That IL-1ra heterozygotes are
developmentally normal suggests that IL-1ra is overabundant in the
unchallenged wt mouse. Consequently, overactive IL-1
signaling (rako) presents a greater danger to overall health
than does elimination of IL-1 signaling (RIko and the
IL-1/ double knockouts) (12, 25, 26).
When we began these studies, a paradox existed because the literature
ascribed different phenotypes to the ratg and
RIko mice that could have indicated that IL-1ra has another
target in addition to the IL-1RI (see above). Overall, our results
eliminate the paradox. On a C57BL/6J genetic background
(n 10), both ratg and RIko
mutants were virtually identical in conferring protection against
septic shock and increasing susceptibility to listeriosis. These
results differ from those previously published and may be due to
differences in genetic background (C57BL/6J for 10 generations vs mixed
B6, 129; or B6, CBA; and C57BL/6J for five generations) or to
differences in experimental methodology (i.p. administration of 10
µg/g LPS from S. typhimurium vs 40 µg/g LPS from
Escherichia coli for septic shock, and
106 vs 104 CFU for
listeriosis). Whatever the exact explanation, our results uphold the
view that IL-1 signaling is an essential regulator of survival in
response to infectious and inflammatory stimuli. Reducing the level of
IL-1 signaling, by elimination of the receptor (RIko) or by
increased expression of IL-1ra (ratg), increases resistance
to systemic inflammation and inhibits innate immune responses. Our
genetic analysis also validates the conclusions of previous studies
using less direct methods, including Ab neutralization and
administration of exogenous recombinant proteins, demonstrating the
essential roles of IL-1 and IL-1ra in these processes (reviewed in Ref.
27). It also raises the possibility that excess IL-1ra, as
prescribed for treating severe rheumatoid arthritis, might increase
susceptibility to infection.
Our analysis of the cytokine network induced by LPS administration
reveals that IL-1 and IL-1ra serum levels are coregulated in vivo even
though their expression is differentially regulated in vitro. In all
the mutant mice examined this coregulation is confined to IL-1 family
of cytokines. This suggests that the parallel levels of IL-1 and IL-1ra
reflect an accumulation of proteins in serum due to competition for
receptor binding that would reduce the level of free cytokine in the
bloodstream, rather than an alteration in de novo protein/mRNA
synthesis that might indicate a global regulation of the cytokine
network itself. Further, these results demonstrate that despite its
potential for autoinduction, IL-1 is not an obligate inducer of itself
in vivo following LPS administration, because IL-1 levels in both
the RIko and ratg mutants (and double mutants)
reach or exceed those of wt mice. Finally, maintaining the
balance between IL-1 and IL-1ra levels is critical to the proper
function of the inflammatory response in vivo. Therefore, it is
necessary to measure the IL-1/IL-1ra ratio, and not simply the absolute
levels of IL-1, to determine accurately the involvement of IL-1 in the
pathogenesis of any disease state.
In all the experimental paradigms we examined, both the ratg and RIko phenotypes were epistatic to the rako phenotype. These results demonstrate that there is no function of IL-1ra independent of the type I receptor and that this function can be fulfilled solely by overexpression of sIL-1ra mRNA. We have been unable to identify any essential role for the icIL-1ra splice variants. However, overexpression of sIL-1ra in ratg mice may mask a contributory role of icIL-1ra during infectious and inflammatory processes, as the ratg phenotype, which differs from that of wt, is seen in the rako, ratg double mutant. Also, the icIL-1ra3 isoform is expressed from the sIL-1ra transgene and may functionally substitute for the alternative splice variants. The question remains of whether sIL-1ra, icIL-1ra3, or both isoforms affect the observed genetic rescue. Our results from the rako, RIko and ratg, RIko double mutants establish that IL-1ra functions exclusively through the IL-1RI. This must be true for both the secreted and intracellular forms. Clearly, intracellular forms must function either by a unique release pathway or be targeted to intracellular functions dependent on the activation of the IL-1RI. However, the simplest model to explain the rako phenotype is a lack of inhibition of IL-1 by sIL-1ra and a resulting chronic overstimulation of the IL-1RI.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David Hirsh, Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail address: dih1{at}columbia.edu
3 Abbreviations used in this paper: IL-1RI, type I IL-1R; IL-1ra, IL-1R antagonist; icIL-1ra, intracellular IL-1ra.
Received for publication March 22, 2002. Accepted for publication April 24, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells for production of IFN- is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J. Immunol. 154:5832.[Abstract]
/ and / T cells from Listeria-infected mice: synergistic effects of interleukin 1 and 7 on / T cells. J. Exp. Med. 178:985., IL-1, IL-1/, and IL-1 receptor antagonist shows that IL-1 is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187:1463.This article has been cited by other articles:
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