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RAPID COMMUNICATION
Interleukin-13 Induces the Production of Interleukin-l Receptor Antagonist
(IL-lra) and the Expression of the mRNA for the Intracellular
(Keratinocyte) Form of IL-lra in Human Myelomonocytic Cells
By Marta Muzio, Fabio Re, Marina Sironi, Nadia Polentarutti, Adrian Minty, Daniel Caput, Pascual Ferrara,
Alberto Mantovani, and Francesco Colotta
The aim of this study was to examine the expressionof
interleukin-l receptor antagonist (IL-lra) in human myelomonocytic cellstreated with IL-13.11-13 inducedIL-lra transcripts in human circulating monocytes and polymorphonuclear cells (PMN). Induction by IL-13 was not blocked, but
rather superinduced,in the presence ofthe protein synthesis
inhibitor cycloheximide. Actinomycin D blocked induction,
suggesting involvement of gene transcription. The half-life
of IL-lra transcriptswas prolongedby IL-13 from 1.3 hoursto
4.5 hours in monocytes andto 12 hours in PMN. By reverse
transcriptase-polymerase chain reaction, IL-13
was found to
augment the transcripts coding for the soluble form of ILIra, but also to induce the expression of the intracellular
(keratinocyte)form of IL-lra, the latter being extremely low
or undetectable in myelomonocyticcells. IL-13 induced production of IL-lra in myelomonocyticcells, augmenting both
cell-associated and released protein. Induction of IL-lra by
IL-13 may represent a further mechanism
by which this molecule can counteract
the potent proinflammatoryproperties
of IL-l.
0 1994 by The American Societyof Hematology.
I
a full secretory peptide, thus remaining almost completely
intracellular (icIL-lra). icIL-Ira mRNA was also found in
fib rob last^,'^ whereas only sIL-lra transcripts were detectable in human PMN andmonocyte^.'^ Purified icIL-Ira had a
biologic activity comparable with sIL- lra," and recombinant
icIL-lra inhibited IL-l -mediated activities in human endothelial cells.I6 The biologic significance of cell-associated
IL-lra is still unclear.
IL- 13 is a recently identified pleiotropic cytokine active
on B cells, mononuclear phagocytes, large granular lymphocytes cells (LGL), and endothelial cell^.^"^^ The IL-13 gene
is located on chromosome 5q 23-3 1, close to the IL-4 gene,
with which itshows about 25% homology." IL-13 resembles
in certain functional aspects IL-4 and IL-IO, in particular in
inhibiting cytokine production by monocytes."
Given the structural and functional similarities between
IL-4 and IL-13, we investigated whether IL-13 induces ILIra. We show that IL-13 induces the expression of the gene
and the production of the proteinof IL-lra in human circulating monocytes andPMN. The concerted action of IL-13
on IL-1 synthesis,I3 production of the IL-1 type I1 decoy
receptor,22.22a
and on production of IL-lra (this report) may
contribute to the antiinflammatory properties of this cytokine.
NTERLEUKIN-la (IL-la) and IL- I/? exert a variety of
effects on different cell types.' IL-I is the only cytokine
for which a specific receptor antagonist, termed IL- 1 receptor
antagonist (IL-Ira), has been identified and cloned.',' IL-Ira
blocks IL-1 activities by its ability to bind, without agonistic
activity, to IL-l receptors of both type I and 11.
IL- Ira is produced by different cell types, including monocyte-macrophages, fibroblasts, keratinocytes, and polymorphonuclear cells (PMN). Monocytes produce IL-Ira when
treated with IgG or immune complexes, lipopolysaccharide
(LPS), granulocyte-macrophage colony-stimulating factor
(GM-CSF), IL-3, and IL-4."9 Mature macrophages constitutively produce IL- Ira and they do not further respond to LPS
or adherent 1gG.I' PMN produce IL-Ira after treatment with
GM- and G-CSF, IL-4, and tumor necrosis factor (TNF),".''
but notwith IL-l/?, interferon-y (IFN-y), or chemotactic
factors." The IL-lra form isolated from monocytes contains
a signal peptide and is thus secreted (sIL-Ira). Nevertheless,
a consistent proportion (up to 50% to 80% in different cell
types) of IL-lra remains cell-associated.'.*
A structural variant of IL-lra, generated by alternative
splicing, is produced by keratinocytes and other epithelial
~ e 1 l s .This
l ~ form of IL-lra has a different 5' end that lacks
From Istituto di Ricerche Farmacologiche "MarioNegri, ' '
Centro Daniela e Catullo Borgomainerio,Miluno, Italy; and Sanoji
Elf Bio Recherches, Lubege, France.
Submitted November 29, 1993; accepted Januury 9, 1994.
Supported by Consiglio nazionale delle Ricerche, pf ACRO, by
'
The Mario Negri-Weizmann Fund, Istituto Superiore di Sunita, V
AIDS Project, and the Associazione Italianu per la Ricerca sul Cancro (AIRC). M.M. and F.R. are AIRC fellows.
Address reprint requests to Francesco Colotta, MD, Istituto di
Ricerche Fumcologiche "MarioNegri," via Eritrea 62, 20157
Miluno, Italy.
The publicarion costs of this article were defrayedin part by page
chargepayment. This article must therefore behereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 I994 by The American Society of Hematology.
0006-4971/94/8307-0033$3.00/0
1738
MATERIALSANDMETHODS
Cell culture reagents and stimuli. The following reagents were
used for culture and separation of cells: pyrogen-free saline (PBS)
and distilled water for clinical use (Bieffe, Bergamo, Italy); RPMI
1640 medium (GIBCO, Glasgow, Scotland); glutamine (GIBCO);
aseptically collected fetal calf serum (FCS; Hyclone, Sterile System,
Logan, UT). The cell culture medium routinely usedwasRPMI
1640 with 2 mmol/L glutamine and 10%FCS (complete medium).
All reagents contained less than 0.125 EUlmL of endotoxin as
checked by the Limulus Amebocyte Lysate assay (Microbiological
Associates, Walkersville, MD).
Human recombinant IL-13 purified from culture supernatants of
stably transfected Chinese hamster ovary (CHO) cell lines was from
Sanofi Elf Bio Recherches (LabBge, France). Actinomycin D (ActD)
and cycloheximide (CH) were from Sigma Chemical CO (St Louis,
MO).
Cells. Circulating human monocytes andPMNwere separated
Blood, Vol83, No 7 (April l),1994: pp 1738-1743
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IL-13 INDUCES THE IL-lra
1739
B
A
IL-13
28 S-
-
1
4
18
MONOCYTES
MONOCYTES
IL-l ra
0
28 S IL-l ra
-
18 S-
PMN
Fig 1. Induction of IL-lra transcripts by IL-13 in human circulating monocytesand PMN. Human purified monocytes andPMN wereincubated
with various dosesof IL-l3 for 4 hours (A) or with 20 ng/mL 11-13 for 1 to 18 hours (B),and then examined for IL-lra transcripts. The ethidium
bromide-RNAs blotted onto membranes are shown.
from normal donors (298% pure as assessed by morphology and
nonspecific esterase staining) by Percoll (Pharmacia, Uppsala, Sweden) gradient centrifugation as described in detail elsewhere?3.'"
Cells were resuspended at 30 X 10' cells/mL in complete medium
and treated with the indicated stimuli at 37°C in 5% CO?. After the
appropriate treatment, cells were examined for IL-lra mRNA or
protein as detailed below.
Northern blot anaLwis. Total RNA was isolated by the guanidine
isothiocyanate method with minor modification^.'^ Ten micrograms
of total RNA was analyzed by electrophoresis through 1% agarose/
formaldehyde gels, followed by Northern blot transfer to Gene
Screen Plus membranes (New England Nuclear, Boston, MA). The
plasmid containing a human IL-Ira cDNA was labeled with aI "P I dCTP (3,000 Ci/mmol; Amersham, Buckingamshire, UK).
Membranes were pretreated and hybridized in 50% formamide
(Merck, Rahway, NJ) with 10% dextran sulfate (Sigma) and washed
twice with 2X SSC (IX SSC: 0.15 molL NaCI, 0.015 molL sodium
citrate) and 1% sodium dodecyl sulfate (SDS; Merck) at 60°C for
30 minutes, and finally washed twice with 0.1 X SSC at room temperature for 30 minutes. Membranes were exposed for 12 to 24 hours
at-80°C with intensifying screens. RNA transfer to membranes
was checked by UV irradiation, as shown in each figure.
Densitometric analysis of autoradiographic signals has been performed with a scanning densitometer apparatus (GS 300; Hoefer
Scientific Instruments, San Francisco, CA).
Reverse transcriptase-polvmerase chain reaction (RT-PCR).
RT-PCR was performed as described." Briefly, 1 pg total RNA
from untreated or IL-13-treated monocytes or PMN was reverse
transcribed in reverse transcriptase buffer ( 5 mmol/L MgC12. 50
mmol/L KCI, 10 mmol/L Tris-HCI [pH 8.3]), with 2.5 pmolL random hexamers, l mmol/L each deoxynucleotide triphosphate, 1 U/
pL RNase inhibitor, and 2.5 U/pL moloney murine leukemia virus
reverse transcriptase (Perkin Elmer Cetus, Nonvalk, CT). Samples
were incubated for 10 minutes at 25°C and then at 42°C for45
minutes. Then each cDNA reaction was divided into three Eppendorf
tubes, and each of them added with a specific pair of primers designed to amplify cDNAs coding for sIL-lra, icIL-Ira and, as an
internal control, human p-actin. Amplification was performed in 2
mmolL MgCI', 50 mmol/L KC]. 10 mmolL Tris-HCI, 0.2 molL
each deoxynucleotide triphosphate, 2.5 U/lOO pL Taq DNA polymerase (Perkin Elmer Cetus), and 4 &mL of each specific primer
(see below). Amplification was performed in an automated thermal
cycler (Perkin Elmer Cetus) at 95°C for 1.5 minutes, at 55°C for 1.5
minutes, and at 72°C for 1.5 minutes. Amplification was stopped at
25 cycles, ie, when amplification of IL-lra transcripts did not reach
the plateau, as assessed in preliminary experiments. Amplified products were run through a 1% ethidium bromide-agarose gel along
with molecular weight standards (Boehringer Mannheim, Mannheim, Germany).
Oligonucleotides were synthesized by the phosphoramidite
method. The sequences of oligos used to selectively amplify sILIra and icIL-Ira were identical to those described." In particular,
we used oligos GM398 and GM344 for sIL-Ira, and oligos GM397
and GM368 for icIL-I ra. Oligos for human p-actin were as reported
by Colotta et aLzs
Detection sf IL-Ira protein. For the quantitative determination
of human IL-Ira we used a specific immunoassay purchased from
Research and Diagnostics Systems (Minneapolis, MN). 30 X 10'
cells per milliliter in complete medium were cultivated with 20 ng/
mL L 1 3 for 18 hours. Cells were centrifuged at 44Og and supernatants tested for released IL-Ira. Cell pellets were resuspended in
lysis buffer (Tris-HCI pH 7.4, 10 mmoVL NaCI. Triton XI00 OS%,
100 U/mL trasilol, 25 pg/mL leupeptin, 0.1 ng/mL pepstatin, 1
mmol/L PMSF; Sigma), and cell lysates tested for cell-associated
IL-lra. Data are expressed as released or cell-associated IL-lra produced by 10' cells.
RESULTS
Human monocytes and PMN were analyzed by Northern
blot for the expressionof L - l r a . As shownin the representative experiment of Fig lA, treatment with 2 to 20 ng/mL
IL-13 induced L - l r a transcriptsin monocytes and PMN.
Heat-inactivatedIL-13 failedtoinduceIL-lra
transcripts
(not shown), thus ruling out endotoxin traces. The two donors shown in Fig l are representative of 10 different donors.
In this series of experiments, induction by IL-13 (10 to 20
ng/mL, 4-hour treatment) of IL-lra transcripts in myelomo-
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MUZlO ET AL
1740
IL-l ra -
MONOCYTES
^.
._ r i
.
_.=_,..- - ..
W
28 S-
IL-l ra -
Fig 2. Effects of metabolicinhibitors on IL-13-induced expression of IL-lra transcripts. Monocytes
and PMN were incubated with IL-13 (20 ng/mL) for
4 hours in the presence or absence of ActD (1 pg/
mL) or CH (10 pg/mL) and then examined for IL-lra
transcripts.
18 S -
PMN
nocytic cells ranged from 2- to 20-fold. Induction by IL-13
of 1L-Ira transcripts in monocytes andPMN was evident
after 1 hour of treatment, peaked at 4 hours, and decreased
after 18 hours of stimulation (Fig 1B).
To obtain information as to the mechanisms involved in
IL-I ra induction by IL- 13, monocytes and PMN were treated
with IL-13 in the presence of metabolic inhibitors. Induction
of IL-Ira by IL-13 in monocytes and PMN did not require
protein synthesis because the addition of the protein synthesis inhibitor CH did not prevent IL-13 activity and. on the
contrary, increased the basal expression of IL- Ira transcripts
and reinforced IL-13-mediated induction (Fig 2). The tran-
IL-13
Act-D
- - 3
6
scriptional inhibitor ActD blocked(in monocytes) or reduced
(in PMN) IL-13-mediated induction of IL-Ira transcripts
(Fig 2).
Then we examined the stability of IL-Ira transcripts in
monocytes and PMN either untreated or treated with IL-13.
As shown in Fig 3, the half-life of IL-lra transcripts in
untreated monocytes and PMN wasapproximately 1.3 hours.
Treatment with IL-13 (4 hours, I O ng/mL) increased the
stability of IL-Ira mRNA,withan
estimated half-life of
approximately 4.5 hours in monocytes and 12 hours in PMN.
A splice variant of IL-Ira transcripts codes for an icILIra." Thus, RT-PCR analysis wasperformedwithappro-
-
+ + + +
8
-
3
6
8
MONOCYTES
(hours)
Fig 3. Stability of IL-lra transcripts in IL-13-treated cells.
MonocytesandPMNwere incubated with or without IL-13 at 20
ng/mL for 4 hours. Then A d D (1
ua/mL) was added for the indicated times and cells examined
for IL-lra transcripts.
.
..,
"
~
'p,
"7,.
28 S -
11-1ra -
18 S -
.-
PMN
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IL-13 INDUCES THE IL-Ira
1741
-+
IL-l3
I
- 653
517
- 453
394
- 296
- 220
- 154
- 1230
- 1033
- 653
- 517
453
monocytes and PMN, we examined the production of the
protein. Cells were incubated with 20 ng/mL IL-13 for 18
hours and then secreted and cell-associated IL-Ira determined by a specific enzyme-linked immunosorbent assay
(ELISA). As shown in Fig 5 , when cells were treated with
IL-13, the production of IL-lra increased both in monocytes
and PMN. In monocytes, IL-13 induced 21.5 ng/106 cells of
secreted IL-lra (mean of 9 donors, range 3.2 to 79.3), and
8 ng/106 cells of cell-associated IL- 1 ra (range I .9 to 19.9).
In PMN, IL-13-treated cells showed 1.7 ng/106 secreted ILIra (mean of 5 donors, range 1.4 to 1.9) and 3.7 @IO6 cells
of cell-associated protein (range 2.6 to 4.8).The secreted
IL-lra, which represented 40.8% and 17.6% of total protein
in untreated monocytes and PMN, accounted for 72% and
32% of total IL-Ira in IL-13-treated monocytes and PMN,
respectively.
Monocytes
- 394
- 296
- 220
secreted
- 154
- 1230
- 1033
- 653
- 517
- 453
394
- 296
- 220
- 154
MONOCYTES
cell-associated
-m
P
1 '
I
I
I
-
11-13
-
I
11-13
PMN
Fig 4. RT-PCR analysis of transcripts codingfor slL-lraand iclL-lra
in IL-13-treated myelomonocyticcells. Cellswere either untreatedor
treated with 11-13 (20 ng/mL) for 4 hours. Then total RNA was extracted and subjectedt o reverse transcription,as detailed in Materials and Methods. The same cDNA
preparationwas divided into three
tubes and each of them amplified, respectively, with specific pairs of
primers designed for slL-lra, iclL-lra, and pactin. An aliquot of the
amplification reactions wasthen analyzed by agarose gel electrophoresis. The figure indicates the expected size of each amplification
product and molecularweight standards run in parallel.
priate pairs of primers to distinguish between transcripts
coding for s L - l r a and icIL-lra. As shown in Fig 4,treatment
with IL-13 (20 ng/mL, 4 hours) augmented the transcripts
for sIL-Ira. RNAs from untreated monocytes andPMN
showed few, if any, transcripts for icIL-lra in monocytes,
and undetectable levels of icIL-lra in PMN. Treatment of
myelomonocytic cells with IL-13 induced icIL-Ira transcripts in both cell types. The specificity of the amplified
products shown in Fig 4 was confirmed by subcloning and
sequencing.
Having found that IL-l3 induces IL-lra transcripts in
PMN
51
U
- 1
secreted
cell-associated
P '
I
-
I
IL-l3
I
-
1
IL-13
Fig 5. Production of IL-lra by IL-13-treated monocytes andPMN.
Cells were incubated with 20 ng/mL IL-13 for 18 hours. Then cell
lysates and supernatants were assayed for IL-lra protein using a
specific ELISA. Data are
from nine (for monocytes) andfive (for PMN)
different donors.
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MUZIO ET AL
1742
2. Arend WP:Interleukin-]antagonist.AdvImmunol
S4:167.
1993
The aim of this study was to investigate the regulation of
3. Arend WP, Joslin FG, Massoni RJ: Effects of immune comIL-Ira by IL-13. Our results indicate that both in monocytes
plexes on production by human monocytes of interleukin 1 or an
and PMN, IL-l3 augmented IL-Ira production and induced
interleukin 1 inhibitor. J Immunol 134:3868, 1985
the expression of the cDNA coding for the icIL-Ira (kera4. Arend WP, Joslin FG, Thompson RC, Hannum CH:
An IL-I
tinocyte) form of IL-Ira.
inhibitor from human monocytes. Production and characterization
of biological properties. J Immunol 143: 1851, 1989
IL-13 augmented the expression of IL-Ira transcripts in
5. EisenbergSP,EvansRJ,
Arend WP,Verderher E, Brewer
monocytes and PMN. While investigating the mechanisms
MT, Hannum CH, Thompson RC: Primary structure and functional
underlying this induction, we found that IL-I3 considerably
expression from complementary DNA of a human interleukin- I reaugmented the stability of IL-Ira transcripts, from 1.3 hours
ceptor antagonist. Nature 343:341, 1990
to 4.5 hours and 12 hours in monocytes and PMN, respec6. Arend WP, Smith MF Jr, Janson RW, Joslin FG: 1L-l receptor
tively. In monocytes IgG induced a marked prolongation of
antagonist and IL- 1 b production in human monocytes are regulated
IL-Ira transcript stability: whereas IL-4 has been reported
differently. J Immunol 147:1530, 1991
to be ineffective in influencing IL-Ira transcript stability.'
7. Poutsiaka DD, Clarck BD, Vannier E, Dinarello CA: ProducAn alternative mRNA coding for an intracellular form of
b by petion of interleukin-l receptor antagonist and interleukin-l
IL-lra is constitutively expressed in cells of epithelial oriripheral blood mononuclear cells is differentially regulated. Blood
gin.I3 The icIL-Ira mRNA was also
found in activated fi78:1272,1991
8. VannierE,MillerLC,DinarelloCA:Coordinated
anti-inbroblasts,'4 in whichLPS preferentially induced sIL-1 ra tranflammatoryeffects of IL-4: IL-4suppressesIL-Iproduction,
but
scripts, whereas PMA selectively induced icIL-lra mRNA.
upregulates gene expression and synthesis of IL-l receptor antagoHere we found that IL-13 was effective in augmenting the
expression of sIL- Ira transcripts, and was also able to induce nist. Proc Natl Acad Sci USA 89:4076, 1992
9. Fenton MJ, Buras JA, Donnelly RP: IL-4 reciprocally regulates
the expression of icIL- Iratranscripts which, in keeping with
IL-l and IL-I receptor antagonist expression in human monocytes.
the original observation," are extremely low (in monocytes)
JImmunol149:1283, 1992
or undetectable (in PMN). Interestingly, the original clone
IO. Janson RW, Hance KR, Arend WP: Production of IL-l recepcodingfortheicIL-Iraformwas
isolated from a cDNA
tor antagonist by human in vitro-derived macrophages. J Immunol
library from induced monocytes." These results indicate that
147:4218, 1991
in addition to cells of epithelial originand fibroblasts, myelo11. McColl SR, Paquin R, Menard C, Bealieu AD: Human neumonocytic cells, when appropriately stimulated, can also extrophils produce high levels of the interleukin 1 receptor antagonist
in responsetogranulocytehacrophagecolony-stimulatingfactor
press the alternative mRNA coding for the icIL- 1ra.
and tumor necrosis factor a. J Exp Med 176593, 1992
Monocytes and PMNsynthetized both cell-associated and
12. Re F, Mengozzi M, Muzio M, Dinarello CA, Mantovani A,
secreted IL- Ira, thus confirming and extending previous obColotta F: Expression of interleukin-] receptor antagonistby human
servations.'.' We found that the majority (up to 90%)of ILcirculating polymorphonuclear cells. Eur J Immunol 23570, 1993
Ira produced by PMN is cell-associated, thus confirming a
13. Haskill S, Martin G, Van Le L, Morris J, Pace A, Bigler CF,
previous report." IL- 13 augmented the total production of
Jaffe GJ, Harnmerberger C, Sporn SA, Fong
S, Arend WP, Ralph
IL-Ira in both monocytes and PMN. In terms of fold inP: cDNA cloning of an intracellular form of the human interleukin
crease, IL- 13 induced preferentially the secreted form of IL1 receptorantagonistassociated
with epithelium.Proc Natl Acad
Ira (see Fig 5). Nevertheless, the majority of IL-Ira in TLSci USA 88:3681, 1991
13-treated PMN still remained intracellular,whereas
in
14. Krzesicki RF, Hatfield CA,Bienkowski MJ, McGuireJC,
Winterrowd GE, ChapmanDL,BergerAE,McEwanRN,Carter
IL-13-treated monocytes up to 72% of total IL-lra was
DB,ChosayJG,TraceyDE,ChinJE:Regulation
of expression
secreted. In PMN"and macrophages")treated with GMof IL-I receptor antagonist protein in human synovial and dermal
CSForTNF,theIL-Ira
synthetizedremainedlargely,
if
fibroblasts. J Immunol 150:4008, 1993
notentirely,intracellular.
By contrast, in LPS- and IgG15. Bigler CF, Noms DA, Weston WL, Arend WP: Interleukinstimulated monocytesup to 80% of total IL-Ira wasse1 receptor antagonist production by human keratinccytes. J Invest
~reted.~.~
Dermatol 98:38, 1992
IL- 13is a recently described cytolunewith multiple activi16. BertiniR,SironiM,Martin-Padura
I, ColottaF,Rambaldi
ties on differentcell
type^.'"^" IL-13shareswithIL-4
a
A, Bernasconi S, Ghezzi P, Haskill SJ, Ralph P, Liu
D, Mantovani A:
series of structural and functionalproperties, including, most
Inhibitory effect of recombinant intracellular interleukin 1 receptor
notably,theinhibition
of cytokine production by human
antagonist on endothelial cell activation. Cytokine 4:44, 1992
monocyte^.'^ The ability of IL-13 to induce the production
17. Minty A, Chalon P, Derocq J-M, Dumont X, Guillemot J-C,
of IL- Ira, in concert with its inhibitory effecton IL- 1 producKhagat M, Labit C, Leplatois P, Liauzun P, Miloux B, Minty C,
Casellas P, Loison G. Lupker J, Shire D, Ferrara P, Caput D: Intion," and induction of the type I1 decoy receptor for
inflammatory
terleukin-13 is a new human lymphokine regulating
IL-Izz.zz"suggest a further mechanism by which IL-13 can
and immune responses. Nature 362:248, 1993
counteract the proinflammatory potentialof IL-l. Thesemul18. McKenzie ANJ, Culpepper JA,
de Waal Malefyt R, Briere
tiple antiinflammatory properties of IL- 13 may be important
F, Punnonen J, Aversa G, Sat0 A, Dang W, Cokcs BG, Menon S,
in modulating the severityof chronic inflammatory disde VriesJE,BancherauJ,Zurawski
G: Interleukin-13, a T-celleases.26
derived cytokinethat regulates human monocyte and
B-cell function.
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IL-13 INDUCES THE IL-lra
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1994 83: 1738-1743
Interleukin-13 induces the production of interleukin-1 receptor
antagonist (IL-1ra) and the expression of the mRNA for the
intracellular (keratinocyte) form of IL-1ra in human myelomonocytic
cells
M Muzio, F Re, M Sironi, N Polentarutti, A Minty, D Caput, P Ferrara, A Mantovani and F Colotta
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