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*
Chrysalis, Princeton, NJ 08540;
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;
Bristol-Myers Squibb, Princeton, NJ 08543; and
§
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B or AP-1-dependent signaling
pathways. Absence of IL-1R AcP differentially affected the affinity for
IL-1 ligands. IL-1R AcP-deficient fibroblasts bound murine IL-1
and
human IL-1R antagonist protein (IL-1Ra) with only moderately reduced
affinity when compared with wild-type cells, whereas murine IL-1ß
affinity was reduced by 70-fold. IL-1 also failed to produce a biologic
response in vivo in IL-1R AcP-deficient mice. These data demonstrate
that a type I IL-1R/IL-1R AcP complex is required for signaling by all
IL-1 agonists and for high affinity binding by IL-1ß. Finally, IL-1R
AcP is an essential signal transducing component of the functional
IL-1R and should represent a novel target for blocking IL-1 function in
human disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß, are capable of binding either
of two confirmed IL-1Rs, the type I and the type II IL-1Rs (IL-1RI and
IL-1RII, respectively) (2, 3). Although the IL-1R
antagonist protein (IL-1Ra) also binds these receptors, it does not
elicit a biologic response. Recently, we have shown that IL-1RI is
critical for IL-1 biologic responses, as IL-1RI-deficient mice are
unresponsive to IL-1 (4), and Abs to the IL-1R block many
responses to IL-1 (5, 6). Conversely, IL-1RII appears to
be a decoy receptor that sequesters IL-1 without signaling and,
consequently, attenuates the IL-1 response (7). The recently cloned IL-1R accessory protein (IL-1R AcP)3 shares approximately 25% amino acid identity to IL-1RI and IL-1RII proteins (8). IL-1R AcP contains three Ig-like domains and a single transmembrane region. IL-1R AcP also has a long cytoplasmic domain homologous to the intracellular domain of IL-1RI, which has been implicated in signal transduction. Furthermore, IL-1R AcP is found in a complex with IL-1RI and the IL-1 agonists, but not with IL-1Ra. Expression of IL-1R AcP has been correlated with responsiveness to IL-1 in a subclone of the murine lymphoma cell line, EL4 (9, 10, 11), and has recently been suggested to be essential for recruitment of IL-1 receptor-associated protein (IRAK) to the IL-1R complex (12). These data suggest that IL-1R AcP may be a second subunit of the IL-1R and that IL-1R AcP and IL-1RI may constitute the functional IL-1.
However, the function of IL-1R AcP remains unclear for several reasons.
First, cells expressing rIL-1R AcP alone do not bind IL-1 (4, 8). Second, the 4C5 mAb, which is specific for murine IL-1R AcP,
blocks IL-1ß binding, but 4C5 has no effect on IL-1 binding or
signaling. 4C5 also inhibits IL-1ß binding to Chinese hamster ovary
(CHO) cells expressing rIL-1RI and IL-1R AcP, yet IL-1RI alone is
sufficient for IL-1 binding. CHO cells that coexpress murine IL-1R AcP
and murine IL-1RI have a 5- to 10-fold increase in IL-1ß-binding
affinity when compared with CHO cells that express the IL-1RI alone
(Kd = 0.257 nM vs Kd =
1.2 nM) (8). Conversely, a recent study failed to identify
a role for IL-1R AcP in IL-1 affinity (11). Other
investigators have suggested that rIL-1RI alone expressed in CHO cells
is sufficient for IL-1-mediated binding and signaling
(13). Finally, the role of IL-1R AcP in IL-1-mediated
biologic responses in vivo has never been addressed.
In order to define its biologic roles, IL-1R AcP-deficient mice have
been produced using gene targeting of embryonic stem cells. IL-1R
AcP-deficient mice are viable but unable to respond to IL-1 or
IL-1ß. Similarly, IL-1R AcP-deficient fibroblasts can bind IL-1 but
also fail to respond to the IL-1 agonists. Loss of IL-1R AcP expression
differentially reduces the affinity of the IL-1RI for the different
IL-1 ligands in these cells. These data demonstrate that IL-1R AcP is
an essential component of the IL-1R.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-1R AcP genomic clones were isolated from a 129Sv genomic
library (Stratagene, La Jolla, CA) using IL-1R AcP cDNA as probe. The
targeting vector was produced by insertion of a 5.5-kb
BamHI-BglII fragment (ending just upstream of D1)
into the BamHI site of pNeoTK and a 1.2-kb PCR-generated
fragment, which starts within the exon encoding D2A into the
ClaI site of the same vector as shown in Fig. 1
. The targeting vector was linearized
with SalI and electroporated into W9.5 embryonic stem cells,
and selection of targeted ES cells was carried out as previously
described (14, 15). ES cells were injected into C57BL/6
blastocysts and implanted into pseudopregnant F1 females.
Chimeric males were bred to F1 females, and heterozygous
offspring were intercrossed. Homozygous IL-1R AcP-deficient mice
appeared normal. Two individual targeted ES cell clones, IL-1R AcP 209
and IL-1R AcP 217, generated separate lines of mice with identical
phenotypes.
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IL-1R AcP heterozygous females were mated to IL-1R AcP heterozygous males. The day of plug was considered day 1 postcoitus. Day 13 postcoitus pregnant females were euthanized and embryos in their yolk sacs were individually separated from maternal uterine tissue (16). Yolk sacs were removed and DNA was prepared from each yolk sac to determine genotype of the embryo. Liver and heart were discarded and the embryonic remains were minced and further digested with trypsin to enhance breakdown to single cell suspensions. Cells from each embryo were separately grown and expanded in primary mouse embryo fibroblast (PMEF) medium containing DMEM, 10% FBS, MEM nonessential amino acids, L-glutamine, pen-strep, and ß-mercaptoethanol. Expanded wild-type (WT) and IL-1R AcP-deficient fibroblast cultures were frozen in PMEF medium with 10% DMSO for later use.
Competitive and equilibrium-binding assays
4C5 and 35F5 Abs and IL-1 were labeled using Iodo-Gen (Pierce,
Rockford, IL) and assays were performed as described (5, 17). WT or IL-1R AcP-deficient cells were plated into Costar
(Cambridge, MA) 12-well plates at 7 x 105 cells/well.
When cells were near confluence, binding experiments were carried out
in 1 ml of binding buffer (RPMI 1640, 5% FBS, and 0.2% sodium azide).
For equilibrium-binding experiments, increasing concentrations of
[125I]4C5 (0.005 to 2 nM) or human
[125I]IL-1 (0.005 to 2 nM) were added either alone
(total binding) or in the presence of 100-fold molar excess of
unlabeled ligand as cold competitor (nonspecific binding). For
competitive binding experiments and determination of inhibitor
dissociation constant (K1), human
[125I]IL-1 (50 pM) was incubated in the presence of
increasing concentrations of unlabeled IL-1 (0 to 30 nM). After 3
h of incubation of 37°C, cells were washed three times with PBS at
4°C and lysed with 0.5% SDS. Lysates were harvested, and bound
radioactivity was determined in an LKB Wallac
counter. Specific
binding was calculated by subtracting nonspecific from total binding.
Incubations were carried out in duplicate or triplicate.
ELISA
Rapidly dividing, subconfluent PMEFs were incubated overnight in
serum-free medium containing DMEM, 20 µg/ml BSA (Boehringer Mannheim,
Indianapolis, IN); and 5 µg/ml transferrin (Sigma, St. Louis, MO).
The following day, PMEFs were treated with the indicated concentrations
of human IL-1, human IL-1ß, or murine TNF in serum-free medium for
12 h. Mouse IL-6 ELISAs were performed in a sandwich format on
anti-mouse IL-6 mAb (0.1 µg/ml, PharMingen, San Diego, CA)-coated
NUNC maxisorp plates. A total of 100 µl of IL-6 standards,
experimental supernatants, or dilutions were incubated at 4°C
overnight, washed, and 100 µl of 2 µg/ml biotinylated
anti-mouse IL-6 IgG (PharMingen) was added to each well.
Streptavidin-peroxidase (1:10,000 dilution, ICN Biomedicals, Cleveland,
OH) was added for 1 h, then 100 µl of K-Blue substrate solution
(Neogen Corp.) was added. The color reaction was stopped by adding 100
µl of 1 M phosphoric acid. Plates were read at 450 nM.
Northern blot analysis
PMEFs were treated with 10 pM IL-1 ligands or 100 ng/mL mouse or
human TNF- (Genzyme, Cambridge, MA) for 4 or 12 h in serum-free
medium. RNA from PMEFs was isolated using the Qiagen (Chatsworth, CA)
Midi RNeasy kit as directed by the manufacturer. A total of 10 µg RNA
in loading buffer containing 40 ng/ml ethidium bromide was loaded per
lane and electrophoresed in 1.2% formaldehyde gels in
morphalinopropanesulfonic acid buffer. RNA was transferred onto
Genescreen Plus membranes (DuPont NEN, Boston, MA) and hybridized to
stromelysin-1, L32, actin, E-selectin, or IL-1R AcP
[32P]dCTP-labeled cDNA probes (Stratagene Prime-It kit)
in 7% SDS and 10 mm Na2PO4. Blots were washed
in 0.2x SSC and 0.5% SDS. Similar experiments were also performed on
mouse tissues recovered from cytokine-treated animals. Northern blot
analysis of IL-1R AcP-deficient mice revealed a truncated IL-1R AcP RNA
produced in tissues of the IL-1R AcP-deficient mice.
In vivo cytokine response
IL-1R AcP-deficient mice or WT siblings were treated i.p. with 2
µg/0.2 ml of either human or murine IL-1 or ß, 1 µg/0.2 ml
murine TNF- (Genzyme) or sterile saline vehicle alone. After 2-h
observation (4 h for TNF-treated mice), whole blood was removed
retro-orbitally from each mouse and IL-6 measured in a B9 cell
proliferation assay as described (18).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the function of IL-1R AcP, IL-1R AcP-deficient mice
were generated by gene targeting in embryonic stem cells. The targeted
mutation deleted the exons encoding the first Ig domain (D1) and part
of the second Ig domain (D2A) (Fig. 1
B). Targeted ES cells
were used to make chimeric mice that bred to produce heterozygous mice.
Analysis of progeny from heterozygous intercrosses identified animals
homozygous for the targeted mutation at the expected mendelian
frequencies (-/-, 67; +/-, 131; +/+: 61). By Southern blot analysis,
the WT+/+ and mutant alleles (-/-) were distinguished by
6- and 4-kb EcoRV fragments, respectively (Fig. 1C). Also, PCR analysis of DNA from homozygous mutant
animals demonstrated that sequences that should have been deleted from
the IL-1R AcP gene were, in fact, absent (data not shown). Homozygous
mutant embryos and adult mice displayed no gross anatomic
abnormalities. Both adult male and female mutant mice were fertile with
average litter sizes of eight pups.
Equilibrium and competitive binding assays
To confirm that the introduced mutation blocked IL-1R AcP
expression, PMEFs were analyzed for cell surface expression of the
IL-1R subunits. We have previously demonstrated that PMEFs from WT mice
express approximately 1500 IL-1RI molecules per cell, but no IL-1RII,
and are highly responsive to IL-1 (4). Expression of IL-1R
AcP was examined by equilibrium-binding studies using radiolabeled 4C5
mAb. Binding of 125I-4C5 to the surface of WT or
heterozygous PMEFs demonstrated that 4C5 mAb binding was specific and
saturable with 
1700 IL-1R AcP molecules/cell (Fig. 2A). Heterozygous fibroblasts
had approximately 1000 IL-1R AcP molecules/cell (data not shown). No
specific binding of 125I-4C5 to the cell surface of
homozygous IL-1R AcP-deficient PMEFs was observed, confirming the
absence of IL-1R AcP expression (Fig. 2B). Also, Northern
blot analysis of IL-1R AcP RNA (data not shown) showed that only a
truncated RNA was produced, which could not encode a functional protein
consistent with the absence of IL-1R AcP protein on the cell surface.
Binding experiments with labeled anti-IL-1RI mAb 35F5 demonstrated
that WT, heterozygous, and IL-1R AcP-deficient cells express
approximately the same number of IL-1RI on their surfaces (1500–3000
sites/cell, as previously published (4); data not shown).
Therefore, IL-1RI is expressed normally on the cell surface in the
absence of IL-1R AcP.
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, C and
D). WT PMEFs specifically bound 125I-labeled
human IL-1 with high affinity (apparent Kd =
30 pM) and expressed approximately 1400 binding sites/cell (Fig. 2C). Although IL-1R AcP-/- cells had
approximately 1600 IL-1 binding sites/cell, these sites exhibited a
single low affinity (apparent KD = 395 pM) (Fig. 2D). Data from six independent experiments confirmed that WT
PMEFs bind human IL-1 with an affinity that is 15 fold higher
than the affinity exhibited by IL-1R AcP-deficient cells (29 ±
4.5 pM vs 505 ± 97 pM, respectively). Our previous data from
transfected CHO cells (8) indicated that the low affinity
sites for IL-1 correspond to IL-1RI and high affinity sites include
IL-1RI/IL-1R AcP complexes (8).
In contrast to human 125I-IL-1 equilibrium-binding
experiments, binding of human and mouse [125I]IL-1ß to
IL-1R AcP-deficient cells was too low to measure accurately.
Accordingly, competitive inhibition assays were used to determine
relative-binding affinities (as apparent Ki) for
all IL-1 ligands when compared with the affinity of
125I-human IL-1 (Fig. 2, E and F).
Similar to the experiment described above, the
Ki for human IL-1 was reduced by 8-fold in
IL-1R AcP-deficient cells. The Ki of human
IL-1ß was slightly more affected by the absence of IL-1R AcP (reduced
by 11-fold). The affinity of murine IL-1 was also reduced but to a
smaller extent (3-fold, apparent Ki of 5.6
and 17 pM, respectively). This observation is in agreement with the
binding affinity of murine IL-1 to the recombinant extracellular
domain of murine IL-1RI. Surprisingly, the binding affinity of murine
IL-1ß was reduced by greater than 70-fold in IL-1R AcP-deficient
cells. Thus, IL-1R AcP serves to increase the affinity of the IL-1RI
for all IL-1 agonists, but differentially affects binding of IL-1
and IL-1ß. Interestingly, human IL-1Ra had an approximately 3-fold
higher Ki on IL-1R AcP-deficient cells. The
significance of this apparent reduction in affinity is unclear as
our previous experiments failed to detect IL-1Ra in an IL-1R AcP/IL-1RI
complex (8).
Biologic responses in IL-1R AcP-deficient fibroblasts
IL-1 and IL-1ß are known to induce expression of a number of
genes, including IL-6 and the matrix metalloproteinase, stromelysin-1.
IL-1 induction of IL-6 is known to be dependent upon nuclear
factor-B, while induction of stromelysin-1 appears to require
activation of c-fos and AP-1 (19, 20, 21, 22, 23, 24). To
determine the role of IL-1R AcP in IL-1-mediated signaling,
IL-1-induced gene expression in WT and IL-1R AcP-deficient cells was
examined (Fig. 3). Treatments with human
IL-1 and IL-1ß led to increased levels of IL-6 secretion from WT
PMEFs (Fig. 3A). Less than 1 pM IL-1 led to significant IL-6
secretion from WT cells. However, IL-1R AcP-deficient PMEFs displayed
no increased IL-6 secretion in response to IL-1 or IL-1ß at
concentrations 500-fold higher than their Kd (up
to 10,000 pM IL-1). Importantly, despite high affinity binding shown
for murine IL-1 to IL-1R AcP-deficient PMEFs (Fig. 2), these
fibroblasts do not secrete IL-6 in response to stimulation by murine
IL-1 (data not shown). Similarly, a significant induction of
stromelysin mRNA was observed in WT PMEFs in response to either IL-1
or IL-1ß, while no stromelysin RNA induction was observed in IL-1R
AcP-deficient PMEFs treated with IL-1 (Fig. 3B). These data
conclusively demonstrate that IL-1R AcP-deficient fibroblasts do not
transduce an IL-1-induced biologic response, even though they bind IL-1
through IL-1RI.
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treatment of either WT and IL-1R
AcP-deficient PMEFs led to increased IL-6 secretion and stromelysin
expression (Fig. 3, A and B). The secreted IL-6
levels produced by TNF--treated WT PMEFs were greater than that
secreted from the IL-1R AcP-deficient cells. Basal levels of
stromelysin RNA or secreted IL-6 from WT cells maintained in serum-free
medium were also higher, compared with mutant PMEFs. These observations
suggested that a significant part of the basal and TNF--induced IL-6
and stromelysin response in WT cells was dependent upon stimulation by
constitutive or induced IL-1 secretion. To test this hypothesis, WT
cells were pretreated with the neutralizing 35F5 anti-IL-1RI mAb to
block signaling through the IL-1RI. This pretreatment reduced the basal
and TNF--induced levels of IL-6 in WT PMEFs to that seen in IL-1R
AcP-deficient PMEFs (Fig. 3A), demonstrating that
constitutive expression of IL-1 was responsible for the basal levels of
IL-6 secretion and that IL-1 contributed to a significant proportion of
TNF-induced IL-6 secretion in these WT cells. Biologic responses to cytokines in IL-1R AcP-deficient mice
The requirement for IL-1R AcP in IL-1-mediated responses was also
examined in vivo (Fig. 4). A
large number of cell types including hepatocytes, fibroblasts,
endothelial cells, and macrophages express IL-6 following IL-1
treatment (1). Serum IL-6 levels were measured in WT and
IL-1R AcP-deficient mice following treatment with human IL-1, murine
IL-1, or TNF- (Fig. 4). As expected, no IL-6 was detected after
injection of saline in WT or mutant mice. IL-1 induced a greater than
100-fold increase in serum IL-6 in WT mice after 2 h. In contrast,
IL-6 was undetectable (<100 IL-6 U/ml) in sera of IL-1- or
IL-1ß-treated IL-1R AcP-deficient mice at 2 h. In addition, no
evidence for induction was obtained at 4 h after IL-1 treatment
(data not shown). Four hours after TNF- injections, substantial
levels of serum IL-6 were detected in both the WT and IL-1R
AcP-deficient mice, demonstrating that the defect in IL-6 induction is
specific for IL-1. In Northern blot analyses of mouse tissues, IL-1
treatments led to increased mRNA expression of the IL-1 inducible,
endothelial-specific E-selectin gene (25) in WT mice, but
failed to induce E-selectin in IL-1R AcP-deficient mice (data not
shown). Therefore, IL-1R AcP is required for IL-1-mediated gene
expression in animals and cultured cells. Finally, these data clearly
show that IL-1R AcP is required for IL-1 signaling in most, if not all,
cell types and that its function cannot be replaced by other members of
the IL-1R gene family.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-1ß. Analysis of IL-1R AcP-deficient cells and mice demonstrate
that the presence of the accessory protein is required for IL-1-induced
expression of IL-6 (nuclear factor-B-dependent), stromelysin
(AP-1-dependent), and E-selectin. These results agree with evidence
that a signaling defect in a mutant T cell line correlates with
aberrant expression of IL-1R AcP (9, 11). In addition, our
studies indicate that IL-1 binding is necessary but not sufficient for
bioactivity. Our original observations made with the inhibitory 4C5 mAb
(8) could not discriminate between binding and signaling
functions for IL-1R AcP. These data clearly show that in the
absence of IL-1R AcP, cells can bind IL-1 through the IL-1RI but
cannot transduce a signal even at saturating concentrations of ligand.
This conclusion is consistent with a recent observation that the
cytoplasmic domain of IL-1R AcP interacts with IRAK. These data clearly
demonstrate that IL-1RI is incapable of signal transduction on its own.
This conclusion is in contrast to that reached in previous studies
(13) with CHO cells expressing rIL-1RI. The enhanced IL-1
biologic responses measured in these CHO cells was most likely due to
the association of an increased number of rIL-1RI molecules with
endogenously expressed IL-1R AcP. Moreover, our studies indicate that a significant portion of IL-6 production in untreated and TNF-treated WT cultured cells is probably mediated by secreted IL-1. Recent studies with Abs to IL-1 and TNF have also indicated the importance of IL-1 in mediating some of the functions of TNF in animal models of inflammation (26, 27). However, after 4-h treatments in vivo, TNF-induced IL-6 responses were similar in IL-1R AcP-deficient and WT mice. More experiments need to be done to determine whether the response to TNF in vivo is quantitatively affected by the loss of IL-1 signaling.
IL-1R AcP appears to play a more significant role in the binding
affinity of the IL-1R complex than previously observed. Our initial
observations suggested a role of transfected IL-1R AcP in increasing
the binding affinity of human IL-1ß for the IL-1RI by about 5-fold
(8). The data presented here demonstrate that IL-1R
AcP-deficient fibroblasts exhibit 3- to 70-fold lower affinities for
murine IL-1 and IL-1ß, respectively, compared with WT cells. This
is in contrast to recent reports, which failed to identify a role for
IL-1R AcP in IL-1 binding (11). We have also generated
mice deficient in IL-1RI that express normal amounts of IL-1R AcP
(4). Cells from IL-1RI-deficient mice do not bind IL-1
ligands, even at concentrations greater than 10 nM. Taken together,
data from the IL-1R AcP-deficient and IL-1RI-deficient mice support our
original model in which the high affinity IL-1R complex is composed of
at least two subunits that together bind IL-1 and induce downstream
events (28, 29, 30, 31). However, the relatively high affinity of
IL-1 to the IL-1RI on IL-1R AcP-deficient cells demonstrates
that IL-1R AcP plays distinct roles in regulating binding affinity and
signaling. IL-1R AcP-deficient cells are now being used to analyze
structure function relationships of domains involved in
receptor heterodimerization, ligand binding, and signal
transduction.
Finally, blockade of IL-1 function has been shown to produce significant benefit in the treatment of inflammatory diseases in animal models and in humans. The studies presented here suggest that IL-1R AcP is essential for the initiation of all IL-1 biologic responses. Thus, IL-1R AcP should provide an effective target for the therapeutic modulation of IL-1-mediated diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mark A. Labow, 556 Morris Avenue, Summit, NJ 07901. E-mail address:
3 Abbreviations used in this paper: IL-1R AcP, IL-1R accessory protein; CHO, Chinese hamster ovary; PMEF, primary mouse embryo fibroblast(s); WT, wild-type; IRAK, IL-1R-associated protein.
Received for publication January 15, 1998. Accepted for publication June 11, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B transcription factor. Mol. Cell. Biol. 10:2327.
B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol. Cell. Biol. 10:561.
B-like sequence. Mol. Cell. Biol. 10:3818.
B binding sites in the human E-selectin gene required for maximal tumor necrosis factor -induced expression. Mol. Cell. Biol. 14:5820.
, anti-IL-1/ß and IL-1Ra. Arthritis Rheum. 39:797.
interferon activation site-like element in the IL-1B gene. Mol. Cell. Biol. 16:2183.
B activation. Proc. Natl. Acad. Sci. USA 93:6721.
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E. K. Brint, K. A. Fitzgerald, P. Smith, A. J. Coyle, J.-C. Gutierrez-Ramos, P. G. Fallon, and L. A. J. O'Neill Characterization of Signaling Pathways Activated by the Interleukin 1 (IL-1) Receptor Homologue T1/ST2. A ROLE FOR JUN N-TERMINAL KINASE IN IL-4 INDUCTION J. Biol. Chem., December 13, 2002; 277(51): 49205 - 49211. [Abstract] [Full Text] [PDF]
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R. Debets, J. C. Timans, B. Homey, S. Zurawski, T. R. Sana, S. Lo, J. Wagner, G. Edwards, T. Clifford, S. Menon, et al. Two Novel IL-1 Family Members, IL-1{delta} and IL-1{epsilon}, Function as an Antagonist and Agonist of NF-{kappa}B Activation Through the Orphan IL-1 Receptor-Related Protein 2 J. Immunol., August 1, 2001; 167(3): 1440 - 1446. [Abstract] [Full Text] [PDF]
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 J.A. Boch, N. Wara-aswapati, and P.E. Auron CONCISE REVIEW Biological: Interleukin 1 Signal Transduction-- Current Concepts and Relevance to Periodontitis Journal of Dental Research, February 1, 2001; 80(2): 400 - 407. [Abstract] [PDF]
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L. E. Jensen, M. Muzio, A. Mantovani, and A. S. Whitehead IL-1 Signaling Cascade in Liver Cells and the Involvement of a Soluble Form of the IL-1 Receptor Accessory Protein ,2 J. Immunol., May 15, 2000; 164(10): 5277 - 5286. [Abstract] [Full Text] [PDF]
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D. E. Smith, B. R. Renshaw, R. R. Ketchem, M. Kubin, K. E. Garka, and J. E. Sims Four New Members Expand the Interleukin-1 Superfamily J. Biol. Chem., January 14, 2000; 275(2): 1169 - 1175. [Abstract] [Full Text] [PDF]
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C.-s. Huang, J. Zhou, A. K. Feng, C. C. Lynch, J. Klumperman, S. J. DeArmond, and W. C. Mobley Nerve Growth Factor Signaling in Caveolae-like Domains at the Plasma Membrane J. Biol. Chem., December 17, 1999; 274(51): 36707 - 36714. [Abstract] [Full Text] [PDF]
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T. L. Born, D. E. Smith, K. E. Garka, B. R. Renshaw, J. S. Bertles, and J. E. Sims Identification and Characterization of Two Members of a Novel Class of the Interleukin-1 Receptor (IL-1R) Family. DELINEATION OF A NEW CLASS OF IL-1R-RELATED PROTEINS BASED ON SIGNALING J. Biol. Chem., September 22, 2000; 275(39): 29946 - 29954. [Abstract] [Full Text] [PDF]
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G. P. A. Vigers, D. J. Dripps, C. K. Edwards III, and B. J. Brandhuber X-ray Crystal Structure of a Small Antagonist Peptide Bound to Interleukin-1 Receptor Type 1 J. Biol. Chem., November 17, 2000; 275(47): 36927 - 36933. [Abstract] [Full Text] [PDF]
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H. Lin, A. S. Ho, D. Haley-Vicente, J. Zhang, J. Bernal-Fussell, A. M. Pace, D. Hansen, K. Schweighofer, N. K. Mize, and J. E. Ford Cloning and Characterization of IL-1HY2, a Novel Interleukin-1 Family Member J. Biol. Chem., June 1, 2001; 276(23): 20597 - 20602. [Abstract] [Full Text] [PDF]
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 C. Shi, X. Zhang, Z. Chen, M. K. Robinson, and D. I. Simon Leukocyte Integrin Mac-1 Recruits Toll/Interleukin-1 Receptor Superfamily Signaling Intermediates to Modulate NF-{kappa}B Activity Circ. Res., November 9, 2001; 89(10): 859 - 865. [Abstract] [Full Text] [PDF]
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