From the Protein Structure Section, Macromolecular
Crystallography Laboratory, Center for Cancer Research,
NCI-Frederick, National Institutes of Health, the
§ Intramural Research Support Program, SAIC-Frederick,
Inc., and the ¶ Cancer and Developmental Biology
Laboratory, NCI-Frederick, National Institutes of Health, Frederick,
Maryland 21702-1201,
Biological Mimetics, Inc., Frederick,
Maryland 21702, and the ** Department of Biochemistry and
Molecular Biology, University of Medicine and Dentistry of New Jersey,
New Jersey Medical School, Newark, New Jersey 07103-2714
Received for publication, August 22, 2002, and in revised form, October 22, 2002
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ABSTRACT |
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Interleukin-19 (IL-19) is a novel cytokine that
was initially identified during a sequence data base search aimed at
finding potential IL-10 homologs. IL-19 shares a receptor complex with IL-20, indicating that the biological activities of these two cytokines
overlap and that both may play an important role in regulating
development and proper functioning of the skin. We determined the
crystal structure of human recombinant IL-19 and refined it at 1.95-Å
resolution to an R-factor of 0.157. Unlike IL-10, which
forms an intercalated dimer, the molecule of IL-19 is a monomer made of
seven amphipathic helices, A-G, creating a unique helical bundle. On
the basis of the observed structure, we propose that IL-19, IL-20, and
other putative members of the proposed IL-10 family together form a
distinct subfamily of helical cytokines.
The identification of
IL-191 as a secreted protein
and a cytokine (1) is based on several features such as its production by immune cells, its ability to be secreted from cells, and its capacity to induce Jak-STAT signal transduction pathway through a
specific receptor complex (1, 2). It has been postulated that IL-19,
IL-10, IL-20, IL-22, IL-24, IL-26, and several virus-encoded cytokines
together form the IL-10 family (3-5).
IL-19 signals through a receptor complex that is also utilized by IL-20
and IL-24 (2, 6, 7). The complex is composed of two chains, CRF2-8 (or
IL-20R1) and CRF2-11 (or IL-20R2; Refs. 2-8), belonging to the class
II cytokine receptor family (9, 10). Receptors from this family also
form heterodimeric complexes for type I and type II interferons and for
other IL-10-related cytokines. Tissue factor, which binds coagulation
factor VIIa, also makes use of receptors belonging to this
family. Binding of IL-19 to the receptor complex results in STAT3
phosphorylation and subsequent activation of a reporter gene controlled
by a minimal promoter containing STAT-binding sites (2).
The transcription of the IL-19 gene has been detected in resting
monocytes and, at lower level, in B cells (11); it is up-regulated in
monocytes stimulated with lipopolysaccharide or granulocyte-macrophage colony-stimulating factor (1, 11). Priming monocytes with IL-4 or IL-13
but not with interferon- Genes encoding IL-10-related cytokines are clustered on human
chromosomes 1 and 12 and possess similar structural organization (4),
indicating that they evolved from a common predecessor. Structural
homology of the genes for IL-10-related cytokines also extends to the
limited homology of amino acid sequences of the cytokines in the
20-40% range. At present, the structures of IL-10 and two of its
virally encoded analogs have been solved, and they represent
intercalating homodimers (12-16). By contrast, the recently solved
structure of IL-22 (17) shows that this cytokine, although a
crystallographic dimer, is a monomer both in solution and as a
biological unit. Here we report the crystal structure of IL-19 (Fig.
1) at the resolution 1.95 Å. Similar to
IL-22 but unlike IL-10, IL-19 was found to be a monomer both in the
solution and in the crystal, and we conclude that the subgroup of
cytokines of which it is a member should be considered structurally
quite distinct from IL-10 itself.
Expression and Purification of IL-19--
Schneider-2 cells were
propagated in Insect Express medium (BioWhittaker, Inc.,
Walkersville, MD) supplemented with 5% fetal bovine serum. The human
cDNA gene encoding interleukin-19 and corresponding to amino
acid residues 1-159 (IL-19, GenBankTM accession number
AY040367) was furnished with a sequence coding for the
Drosophila signal peptide followed by a
His6 affinity purification tag. An artificial opal TGA stop
codon was engineered at the 3' end of the expression fragment along
with KpnI and EcoRI restriction sites on its 5'
and 3' ends, respectively. The construct was cloned into the
constitutive insect cell expression vector pAc5.1/V5-HisA (Invitrogen).
Schneider-2 cells (~1 × 106 cells) were
co-transfected with the resulting vector and pCo-Hygro (Invitrogen)
using the cationic lipid Maxfect (Molecular Research Laboratories,
Inc., Herndon, VA). Every 3 days following transfection, culture medium
containing hygromycin B (300 µg/ml) was refreshed. Drug selection
continued in tissue culture plates and flasks until the
hygromycin-resistant population had expanded to ~1 × 108 cells. After selection, the cells were propagated as
spinner cultures at cell densities between 1 × 106/ml
and 5 × 107/ml without antibiotics. Conditioned
supernatants containing recombinant IL-19 were concentrated and
dialyzed against 20 mM sodium phosphate buffer, 0.5 M NaCl, pH 7.0 (buffer A). Purification was carried out by
using a HiTrap Chelating 5-ml column charged with Ni2+.
Protein solution was put on the column with a peristaltic pump at a
flow rate of 2 ml/min. The column was washed extensively with buffer A
followed by buffer A plus 10 mM imidazole; elution of the
protein was accomplished with buffer A plus 50 mM
imidazole. The final material was obtained by Superdex 75 gel
filtration in 50 mM HEPES, 200 mM NaCl, pH 7.0. A STAT activation electrophoretic mobility shift assay showed
that the protein was fully active in comparison with IL-19 produced by
COS cells.
Crystallization, Data Collection, and Structure
Determination--
Crystallization conditions were initially found
from Hampton Research crystallization kit I at 21 °C, tube number 4. However, final crystals were obtained by the hanging drop method in 100 mM HEPES, 1.9 M ammonium sulfate, 2%
polyethylene glycol 400, pH 6.9. The protein concentration was 7 mg/ml.
Crystals were grown for 2 months and were flashed in 25% (w/v)
glycerol/well solution before freezing at 100 K. Diffraction data for
both the native crystals and heavy atom derivatives were collected on a
MAR-345 image plate system coupled with an RU-200 x-ray generator.
Crystals belong to the orthorhombic system, space group
P212121, with one molecule/asymmetric unit. Unit cell parameters are a = 30.7 Å, b = 53.0 Å, and c = 93.5 Å.
The programs DENZO and SCALEPACK (18) were used for data processing.
Phase determination was carried out with the programs PHASES (19) and
SOLVE/RESOLVE (20) by using two isomorphous derivatives at 3.5-Å
resolution (Table I). An electron density
map obtained using RESOLVE allowed us to generate the initial
model, which contained about 60% of the amino acid residues.
The rest of the molecule was placed during alternating cycles of
refinement and map fitting. The refinement at high resolution was
carried out with the software program CNS (21), and the maps were
fitted with the program O (22). The final model contains residues
4-104 and 108-159, 164 water molecules, and a single N-acetylglucosamine attached to Asn38. The
coordinates have been deposited in the Protein Data Bank (accession
code 1N1F).
Description of IL-19 Molecule--
The crystal structure of IL-19
was solved by a multiple isomorphous replacement technique by
using two heavy atom derivatives (Table I) at the resolution 3.5 Å and
was later refined using full resolution of the available data (1.95 Å). The final structure consists of residues 4-104, residues
108-159, and 164 water molecules. All residues have conformations
corresponding to either most favorable (93%) or allowed (7%) regions
on the Ramachandran plot (Fig. 2). Of the
two predicted glycosylation sites, Asn38 and
Asn117, only the former was found to be occupied, whereas
the latter does not appear to bind any oligosaccharide. The conclusion
is based both on the lack of electron density, which could be
identified as an oligosaccharide (Fig.
3), and on the observed
interactions of the side chain of Asn117. Its OD1 atom
makes a hydrogen bond to NH1 of Arg120, whereas the ND2
atom is hydrogen-bonded to the carbonyl oxygen of Gln113
and to a bridging water molecule in the intermolecular interface. We
were able to identify only the first N-acetylglucosamine
moiety linked to the ND2 atom of Asn38. Even though some
weak electron density beyond this saccharide suggested the presence of
additional sugars, it was impossible to locate them unambiguously in
the electron density because they probably have multiple conformations.
In fact, even the first N-acetylglucosamine very likely
adopts several conformations, although the orientation that we found is
clearly the major one, corresponding to an occupancy rate of about
70%.
A molecule of IL-19 is a monomer made up of seven amphipathic helices,
A-G, of different lengths (Fig. 1a), forming a unique seven-helix bundle with an extensive internal hydrophobic core. Three
disulfide bridges located on the top of the bundle make the polypeptide
chain framework quite rigid. Most of the helices adopt
3.613 and 310 conformations; however, kinks are
seen in helices B and G, and a Comparisons with Related Cytokines--
Because IL-19 is a
monomer, whereas IL-10 is an intercalated dimer consisting of two
identical domains, we superimposed the coordinates of IL-19 onto one of
the domains of IL-10. The root mean square deviation between the
positions of C
A BestFit (24) comparison of the amino acid sequences of IL-19 and
IL-10 shows 21% identity (30 residues) and 37.5% similarity, whereas
the identity and the similarity between IL-20 and IL-10 are 29.5 and
47.3%, respectively. In both cases the identity/similarity begins at
position 22 of IL-10, corresponding to the beginning of helix B of
IL-19 and, very likely, of IL-20 as well. A comparison of IL-19 and
IL-20 gives even better sequence homology between them (44.1%
identity, 52.4% similarity) without any gaps or deletions, starting
earlier in the sequence (Fig. 5) at the
position corresponding to helix A of IL-19. It is interesting that to
achieve the best quality of alignment, one only needs to shift the
amino acid sequence of IL-20 four positions to the left along the
sequence of IL-19 (Fig. 5). The superposition of the sequences of all
three proteins shows a remarkable degree of similarity in the positions
of hydrophobic residues and of the cysteines involved in the formation
of the disulfide bridges. In fact, all three disulfide bonds present in
IL-19 are also preserved in IL-20. We must conclude that, taken together, the three-dimensional structure of IL-20 must be similar to
IL-19, and it is no surprise that these two cytokines share their
receptors. The only obvious difference between IL-19 and IL-20, besides
their N termini, is expected at the C terminus in the region of the
C-terminal
The identity between IL-19 and IL-24 (MDA-7) is slightly
lower at 31% with 40% similarity. Interestingly, the latter cytokine has only two cysteines (Cys16 and Cys63),
corresponding to Cys10 and Cys57 of IL-19.
Since these two cysteines are involved in making separate disulfide bonds and their C
The sequence similarity between IL-19 and IL-22 is not as high as the
sequence similarity between either IL-19 and IL-20 or IL-19 and IL-24;
however, there is still 36% sequence similarity if the gap penalty
(24) is allowed to be lower. A superposition of the structures of IL-19
and IL-22 (17) results in a root mean square deviation of 1.7 Å for
123 pairs of C Receptor-binding Sites--
The functional IL-10 ligand-receptor
complexes contain a dimer of ligands, two copies of the IL-10R1
subunit, and likely two copies of the IL-10R2 subunits (Fig.
6; Refs. 8, 26, and 27). In the case of
IL-19, two subunits, IL20-R1 and IL-20R2, are required to assemble a
functional receptor complex. Although it is not clear yet what sequence
of events takes place on the cell surface, it is known that IL-19 makes
a stable ternary complex with both receptors at the same time (2). This
is similar to what has been shown for the binding of IL-20 with IL-20R1
and IL-20R2 (7). Nevertheless, because the superposition of IL-19 onto
one domain of the dimer of IL-10 is so good (Fig. 4), it is
appropriate to speculate that the receptor-binding site on IL-19
surface should be somewhat similar to that of IL-10. We marked the receptor-binding site of IL-19 by using crystal structure of
the complex of IL-10 with its soluble non-glycosylated mutant of
IL-10R1 (27). It is interesting that a simple substitution of the IL-10
domain with IL-19 in the structure of the IL-10/IL-10R1 complex gives a
quite reasonable model for ligand/receptor interactions. The only clash
occurs between Glu46 of IL-10R1 (loop L2) and
Asn38, which is the glycosylation site of IL-19 with
attached oligosaccharide. There are also a few close contacts in the
area of the C-terminal strand of IL-19 and loops L5 and L6 of the
receptor. Table II shows all
residues of IL-19 within the range of 5 Å from the receptor. Residues
interacting with the receptor are located on helix B, loop BC,
helix C, helix G, and the C-terminal IL-19 Defines a Distinct Subfamily of Cytokines--
IL-19 shares
20-40% sequence identity with other members of the postulated family
of IL-10-related cytokines; members of this family include IL-10,
IL-20, IL-22, IL-24, and IL-26 (3, 4, 28). The expression of the IL-19
gene appears to have complex regulation. It is likely that there are
two alternative promoters that may be differentially regulated. IL-19
transcripts produced from these promoters differ in their 5'
untranslated regions. Translation of the IL-19 mRNA with the
shorter 5' untranslated region generates IL-19 protein with a classical
signal peptide, which is predicted to be 18 amino acids long and to
yield Ser as a first amino acid of the secreted mature IL-19 protein.
However, an alternative 24-residue-long signal peptide has been
annotated in the Swiss Protein Database under Swiss-Prot
accession number Q9UHD0. Until now, the identity of the first amino
acid of the mature protein has not been determined
experimentally, although the N terminus at position 19 is more likely
based on the similarity with IL-10. The longer 5' sequence contains an
additional ATG codon in-frame with the main peptide sequence.
Initiation of translation from this potential alternative ATG codon
produces protein with a long abnormal signal peptide affecting its
secretion. We expressed IL-19 corresponding to a normal length signal
peptide, with Ser as the first residue and the whole protein 159 residues long. There are two potential sites for N-linked
glycosylation, Asn38-Val39-Thr40
and Asn117-Ala118-Thr119,
although we found that only the Asn38 site is occupied by
an oligosaccharide.
IL-19, together with IL-10 and the other cytokines mentioned above, are
members of the class of long helical cytokines (25) that utilize class
II receptors. Another member of that class is interferon-
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
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significantly increases the levels of IL-19
mRNA induced by subsequent lipopolysaccharide treatment (1). IL-19
mRNA also has been detected in Epstein-Barr virus-transformed lymphocytes (1, 11), suggesting that viral infection can induce IL-19 expression in certain cells. The pattern of
expression of IL-19 receptor subunits can reveal the site for IL-19
action. Because the simultaneous presence in a cell of both receptor
subunits CRF2-8 (IL-20R1) and CRF2-11 (IL-20R2) is required for IL-19
activity, only tissues in which the expression of both subunits has
been detected can be considered a potential target for IL-19 action.
IL-20R2 has a more limited pattern of expression than IL-20R1 (7), and
thus the expression of IL-20R2 should be a limiting factor dictating
the physiological sites of action of IL-19. Expression of mRNAs for
both receptors, although at different levels, has been detected in the
skin, testis, ovary, heart, lung, muscle, placenta, adrenal gland,
small intestine, and salivary gland (7). The expression of the IL-19
receptor subunits in skin is of a particular interest because it has
been found to be up-regulated in psoriatic skin, whereas normal skin has low levels of receptor expression. The expression of receptors also
has been detected in keratinocytes, endothelial cells, and immune cells
in psoriatic lesions. Moreover, IL-20-transgenic mice die within days
after birth with skin abnormalities characteristic for psoriasis (7).
Sharing of the same receptor complex by both IL-19 and IL-20 suggests
that IL-19 should have overlapping biological activities with IL-20 and
thus may be a player in psoriatic lesions. Therefore, the pattern of
expression of IL-19 and its receptors suggests that this cytokine may
be involved in the regulation of inflammatory responses in various
tissues and may be particularly important for proper skin development
and functioning.
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Fig. 1.
Crystal structure of IL-19.
a, stereo tracing of the C atoms of IL-19. The
backbone is shown in green, the disulfide bridges are shown
in yellow, and the
helices are labeled as
A-G. b, stereo ribbon representation
of IL-19.
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EXPERIMENTAL PROCEDURES
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Data collection, phasing, and refinement statistics
RESULTS AND DISCUSSION
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ABSTRACT
INTRODUCTION
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Fig. 2.
Ramachandran plot for the final structure of
IL-19.
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Fig. 3.
The final 2Fo Fc electron density map in the area of the
second putative glycosylation site,
Asn117. Atoms are
color-coded as follows: carbon atoms are green,
nitrogen atoms are blue, and oxygen atoms are
red. All residues and water molecules belonging to the
symmetry-related molecules are violet. Possible interactions
of the side chain atoms of Asn117 (distances less than 3.5 Å) are shown as dashed lines. The contour level is 1.0
.
Wat, water.
-helical turn is present in helix D. Helices B, D, E, and G make a four-helix bundle, which is a
characteristic feature of all helical cytokines (23). The position of
helix A, which covers the top of the molecule, is stabilized by the disulfide bridge Cys10-Cys103, linking it
covalently to the C terminus of helix E. The second and third disulfide
bridges, Cys57-Cys109 and
Cys58-Cys111, hold together the N terminus of
helix D, the interhelical loop EF, and the N terminus of helix F. The
C-terminal strand 154-159 is bent along the surface of the molecule
and makes hydrogen bonds with the short interhelical strand AB. These
two parallel strands form a short
-sheet never seen previously in
helical cytokines (Fig. 1b). Temperature factors for the
protein average 37.2 Å2, whereas those for the solvent are
52.5 Å2. The highest temperature factors, indicating
considerable flexibility of the molecule, are found at the N terminus
and, surprisingly, in the region that contains two cysteines involved
in forming separate disulfides (residues 103 and 109). Residues
105-107 were not placed in the final model, although some scattered
electron density is seen in the area where they might be located. It is likely that these residues exhibit multiple conformations for both the
main chain and the side chains, and thus their structure remains
presently undefined.
atoms is only 1.7 Å, and it can easily be improved
even further if we remove the N-terminal 14 residues of IL-19 (helix
A), the first 21 residues of IL-10, the C-terminal 6 residues, and a
few residues in the interhelical loops, particularly at the top of the
molecule (Fig. 4). The orientation of
helix E (helix D of IL-10) relative to the rest of the helical bundle
is also different, with the root mean square deviation at its N
terminus being about 1 Å and increasing to 3.8 Å at its C terminus.
The general architecture of these molecules is very much alike,
although the orientation of the new helix A and the short
-sheet in
the IL-19 make the overall shape of the molecule more compact and
smooth.
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Fig. 4.
Stereo diagram of the superposition of IL-19
with a single domain of IL-10. Ribbons are
cyan, coils are brown, and -strands are
green. IL-10 is represented in pink, and
disulfide bonds are shown in yellow.
-strand of IL-19. There is no such strand in IL-20
because Glu157, the last residue of IL-20, corresponds to
His153 of IL-19, which is the last residue in the helix
G.
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Fig. 5.
Sequence alignment of IL-10
(top), IL-19 (middle), and IL-20
(bottom). Conservative hydrophobic residues
are marked in red, whereas cysteines are green.
Helices of IL-10 and IL-19 are shown in cyan and
red, respectively.
positions are 8.6 Å apart, this must indicate either that IL-24 forms a monomer with a very unique conformation of the N terminus, bringing Cys16 into the
proximity of Cys63 to form a disulfide bridge between them,
or that IL-24 is a dimer stabilized by inter-monomer disulfide bridges
similar to those found in the structure of the cytomegalovirus homolog
of IL-10 (16).
atoms. This value is almost identical to the results
of the superposition of IL-19 and IL-10, although the overall
similarity appears to be higher because of the monomeric nature of both
molecules. Whereas the disulfide bridge
Cys10-Cys103 of IL-19 corresponds to the
disulfide bridge Cys7-Cys99 of IL-22,
they are also significantly shifted (2.5-5.5 Å for the respective
C
coordinates). Although IL-19 Cys57 is equivalent in
sequence to Cys56 of IL-22, their C
coordinates are 3.3 Å apart, and their disulfide partners are different. A similar
variability of the disulfides has previously been reported for
short-chain helical cytokines (25). Another structural feature very
highly conserved between these cytokines is a salt bridge formed
between Lys27 and Asp143 and located on the
surface of the molecule. This bridge is strictly conserved in IL-19,
IL-10, IL-22, and IL-24, with a mutation to Arg in IL-20.
-strand, including carboxyl
oxygens. It is very likely that one of the receptor interaction sites
in IL-19 is similar to that in IL-10. Whether this site contacts
the IL-20R1 or IL-20R2 subunit of the IL-19 receptor complex remains to
be seen.
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Fig. 6.
Schematic diagram of the IL-10 and IL-19
receptor complexes. a, an IL-10 homodimer interacts
with four receptor subunits, two molecules of IL-10R1, and two
molecules of IL-10R2. b, an IL-19 monomer is likely to
signal through heterodimeric receptor complexes consisting of IL-20R1
and IL-20R2 subunits.
Amino acid residues of IL-19 within the range of 5 Å from the receptor
. Whereas
IL-10 and interferon-
form intercalating noncovalent homodimers
(12-14, 29), IL-19 is monomeric. The structure presented here shows
that IL-19 is a compact, seven-helix bundle with an extensive
hydrophobic core inside. It is very likely that IL-20 has a very
similar structure, as does IL-22. The other two newly discovered
homologs of IL-10 (IL-24 and IL-26) are probably homodimers, as
reported directly for IL-26 (30). Our analysis of the amino acid
sequence of IL-24 suggests that this cytokine could be a covalently
bound dimer. IL-24 has only two cysteines, Cys16 and
Cys63. Provided that its three-dimensional structure is
similar to that of IL-10, it is very likely that Cys63,
located at the N terminus of helix C (IL-10 notation), makes a
disulfide bridge with Cys63 of the second monomer in a
manner similar to what has been seen in the structure of the
cytomegalovirus homolog of IL-10 (16). In this case
Cys16 would be left free, a very unusual arrangement for
helical cytokines. For that reason, we postulate that there is still a
possibility that Cys16 could somehow be positioned in the
proximity of Cys63 and form a disulfide bridge with it. In
this case IL-24 would be a monomer similar to IL-19. We may conclude
that, taken together, IL-19, IL-20, IL-22, and probably also IL-24
could be united in a single subfamily of helical cytokines.
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FOOTNOTES |
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* This work was supported in part by NCI, National Institutes of Health Contract NO1-CO-12400.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The atomic coordinates and the structure factors (code 1N1F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
To whom correspondence should be addressed: Macromolecular
Crystallography Laboratory, NCI-Frederick, P. O. Box B, Frederick, MD
21702-1201. Tel.: 301-846-5344; Fax: 301-846-7101; E-mail: zdanov@ncifcrf.gov.
Published, JBC Papers in Press, October 25, 2002, DOI 10.1074/jbc.M208602200
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ABBREVIATIONS |
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The abbreviations used are: IL, interleukin; STAT, signal transducers and activators of transcription; CRF, corticotropin-releasing factor; R1, receptor 1; R2, receptor 2.
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