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From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 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 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 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- From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 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 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 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. From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 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. REFERENCES Proc Natl Acad Sci USA 90:3735, 1993 19. Punnonen J, Aversa G, Cocks BG, McKenzie ANJ, Menon 1. DinarelloCA:Interleukin-landinterleukin-lantagonism. S, Zurawski G, de WaalMaleftyR, de VriesJE:Interleukin-l3 Blood 77:1627, 1991 DISCUSSION From www.bloodjournal.org by guest on June 18, 2017. For personal use only. IL-13 INDUCES THE IL-lra induces interleukin-4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Roc Natl Acad Sci USA 90:3730, 1993 20. Herbert JM, Savi P, Laplace M-C, Lalt A, Dol F, Dumas A, Labit C, Minty A: IL-4 and IL-13 exhibit comparable abilities to reduce pyrogen-induced expression of procoagulant activity in endothelial cells and monocytes. FEBS Lett 328:268, 1993 21. McKenzie ANJ, Li X, Largaespada DA, Sato A, Kaneda A, Zurawski SM, Doyle EL, Milatovich A, Francke U, Copeland NG, Jenkis NA, Zurawski G : Structural comparison and chromosomal localization of the humanand mouse IL-13 genes. J Immunol 150:5436, 1993 22. Colotta F, Re F, Muzio M, Bertini B, Polentarutti N, Sironi M, Giri JG, Dower SK, Sims E, Mantovani A Interleukin-l typeII receptor: Science 261:472, 1993 A decoy target for IL-1that is regulated byW. 22a. Colotta F, Re F, Muzio M, Polentamtti N. Minty A, Caput D, Ferrara C, Mantovani A: IL-13 induces expression and release 1743 of the IL-1 decoy receptor in human polymorphonuclear cells. J Biol Chem 1994 (in press) 23. Colotta F, Pen G, Villa A, Mantovani A: Rapid killing of actinomycin D-treated tumor cells by human mononuclear cells. I Effectors belong to the monocyte-macrophage lineage. J Immunol 132:936, 1984 24. Bertani A, Polentarutti N. Suca A, Rambaldi A, Mantovani A, Colotta F Expression of c-jun protooncogene in human myelomonocytic cells. Blood 74181 1, 1989 25. Colotta F, Polentarutti N, Sironi M, Mantovani A Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J Biol Chem 267:18278, 1992 26. Allen JB, Wong HL, Costa GL, Bienkowski MJ, Wahl SM: Suppression of monocyte function and differential regulation of IL-1 and IL-lra by IL-4 contribute to resolution of experimental arthritis. J Immunol 151:4344, 1993 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 Updated information and services can be found at: http://www.bloodjournal.org/content/83/7/1738.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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