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Resting Primary Macrophages by IL-10 Shaping Gene Expression In Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10 Roland Lang, Divyen Patel, John J. Morris, Robert L. Rutschman and Peter J. Murray This information is current as of October 2, 2021. J Immunol 2002; 169:2253-2263; ; doi: 10.4049/jimmunol.169.5.2253 http://www.jimmunol.org/content/169/5/2253 Downloaded from References This article cites 44 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/169/5/2253.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-101 Roland Lang,* Divyen Patel,2† John J. Morris,† Robert L. Rutschman,* and Peter J. Murray3* IL-10 regulates inflammation by reducing cytokine and chemokine production from activated macrophages. We performed microarray experiments to identify possible effector molecules of IL-10 and to investigate the global effect of IL-10 on the transcriptional response induced in LPS-activated macrophages. To exclude background effects of endogenous IL-10, macro- phages from IL-10-deficient mice were used. IL-10 up-regulated expression of a small number of genes (26 and 37 after 45 min and 3 h, respectively), including newly identified and previously documented targets such as suppressor of cytokine signaling-3 and IL-1 receptor antagonist. However, the activation program triggered by LPS was profoundly affected by IL-10. IL-10 repressed 62 and further increased 15 of 259 LPS-induced genes. For all genes examined, the effects of IL-10 were determined to be STAT3-dependent. These results suggest that IL-10 regulates STAT3-dependent pathways that selectively target a broad com- ponent of LPS-induced genes at the mRNA level. The Journal of Immunology, 2002, 169: 2253–2263. Downloaded from nterleukin-10 is an essential anti-inflammatory cytokine pro- cells and up-regulated on macrophages upon activation (1, 2). This duced primarily from T cells and activated macrophages. fact, combined with genetic evidence from a variety of animal I IL-10 is capable of blocking or reducing the output of nu- model systems, supports the notion that macrophages are the pri- merous proinflammatory agents from macrophages including cy- mary target of IL-10 (10, 11). Binding of IL-10 to its receptor tokines such as TNF-␣, IL-6, and IL-12, chemokines, and prosta- initiates signaling via the Janus kinase-STAT pathway. Limited http://www.jimmunol.org/ glandins via blocking cyclooxygenase 2 expression (1, 2). Because studies using fetal liver-derived Janus kinase 1-deficient macro- of these broad effects, IL-10 has elicited considerable clinical in- phages (12) suggest this kinase is essential for early IL-10 signal- terest to treat chronic inflammatory conditions such as Crohn’s ing. STAT3 plays a pivotal role because the conditional inactiva- disease (3) and hepatitis C-induced fibrosis (4). tion of STAT3 in myeloid lineage cells results in abrogated IL-10 No consensus has emerged as to how IL-10 inhibits production responses of macrophages and development of chronic enteroco- of cytokines and chemokines from macrophages. Inhibition of litis similar to IL-10-deficient (IL-10Ϫ/Ϫ) mice (11). TNF-␣ production by IL-10, for example, has been attributed to It is not known how IL-10 attenuates macrophage activation effects on NF-␬B activation (5), mitogen-activated protein kinase downstream of STAT3. Experimental evidence suggests that new (MAPK)4 signaling pathways (6), rate of transcription (7), mRNA protein synthesis is required for IL-10 to inhibit LPS-induced cy- by guest on October 2, 2021 stability (8), translational efficiency (6), cleavage from the mem- tokine production, since IL-10 does not appear to inhibit IL-12 p40 brane, and uptake via TNF receptors (9) (for reviews, see Refs. 1 or TNF-␣ expression in LPS-stimulated macrophages when cyclo- and 2). Also, conflicting results have been reported for most of heximide is added (8, 13). To date, few genes have been described these effects. In contrast, genetic and biochemical analysis has elu- to be induced by IL-10. We reasoned that a gene expression screen cidated the membrane proximal events of IL-10 signaling. The for IL-10-induced genes in macrophages should identify a range of functional IL-10R consists of the ligand binding IL-10R1 and the targets potentially involved in deactivation of macrophages. We took accessory subunit IL-10R2 (1, 2). Although IL-10R2 is expressed advantage of macrophages from mice deficient in IL-10 or STAT3 on most cells and tissues, IL-10R1 is expressed on hemopoietic and microarray techniques to identify and validate genes induced and repressed by IL-10 in resting and activated macrophages. *Department of Infectious Diseases and †Hartwell Center for Biotechnology and Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN 38015 Materials and Methods Received for publication April 8, 2002. Accepted for publication June 18, 2002. Reagents, mice, and macrophages The costs of publication of this article were defrayed in part by the payment of page IL-10 and IL-4 were purchased from BD PharMingen (San Diego, CA), charges. This article must therefore be hereby marked advertisement in accordance LPS was obtained from Sigma-Aldrich (St. Louis, MO). IL-10Ϫ/Ϫ mice with 18 U.S.C. Section 1734 solely to indicate this fact. (14) on a C57BL/6 background and controls were purchased from The Ϫ 1 This work was supported by American Heart Association Grant 0151039B to Jackson Laboratory (Bar Harbor, ME). STAT3flox/ and LysMcre breeding P.J.M., Cancer Center CORE Grant P30 CA 21765, and by the American Lebanese pairs were a gift from I. Fo¨rster (Technical University of Munich, Munich, Syrian Association of Charities. R.L. was a recipient of a fellowship from the Deut- Germany). Peritoneal-derived macrophages (PDM) and bone marrow-de- sche Forschungsgemeinschaft (LA-1262/1). rived macrophages (BMDM) were isolated as previously described (10). 2 Current address: Boling Center, 711 Jefferson Avenue, No. 415, Memphis, TN Detection of IL-10 and TNF-␣ in culture supernatants was by ELISA using 38163. Ab pairs from BD PharMingen. 3 Address correspondence and reprint requests to Dr. Peter J. Murray, Department of Infectious Diseases, St. Jude Children’s Research Hospital, 332 North Lauderdale, Affymetrix gene chip analysis Memphis, TN 38105. E-mail address: [email protected] Ϫ/Ϫ 4 IL-10 BMDM were stimulated with IL-10 (10 ng/ml), LPS (100 ng/ml), Abbreviations used in this paper: MAPK, mitogen-activated protein kinase; PDM, or IL-10 ϩ LPS for 45 min or 3 h. For both timepoints, two completely peritoneal-derived macrophages; BMDM, bone marrow-derived macrophages; IL- 1ra, IL-1R antagonist; SOCS, suppressor of cytokine signaling; GADD, growth arrest independent experiments were performed. Total RNA was prepared using and DNA damage; EST, expressed sequence tag; JE/MCP, JE/monocyte chemoat- TRIzol (Life Technologies, Gaithersburg, MD), processed, and hybridized tractant protein; Tpl, tumor progression locus; TLR, Toll-like receptor; C/EBP, to MG-U74Av2 gene chips according to Affymetrix protocols (Santa Clara, ␣ CCAAT/enhancer binding protein; AMBP, 1-microglobulin/bikunin precursor. CA). Chips were scanned and analyzed using Affymetrix Microarray Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 2254 TARGET GENES OF IL-10 IN MACROPHAGES Suitev4.0 software. Sample loading and variations in staining were stan- critical determinants of the results obtained by gene expression dardized by scaling the average of the fluorescent intensities of all genes on profiling. We analyzed the influence of these variables on inhibi- an array to constant target intensity (2500) for all arrays used. The signal tion of TNF-␣ production by IL-10 to establish conditions optimal intensity for each gene was calculated as the average intensity difference, represented by (⌺(PMϪMM)/(number of probe pairs)), where PM and to identify IL-10-induced genes and investigate its overall impact MM denote perfect-match and mismatch probes. on the transcriptional response to LPS. In response to LPS, both BMDM and PDM rapidly produced TNF-␣ that was inhibited by Data analysis IL-10 as expected (Fig. 1). However, PDM made more TNF-␣ and Data sets of 12,488 probe sets per array were compared using Microsoft showed a stronger inhibitory effect of IL-10. This difference was Excel (Microsoft, Redmond, WA) and Spotfire software. To avoid negative inversely correlated with much higher production of IL-10 in Ͻ ratios, average intensity differences 5 were first set to 5 (15). Data were BMDM, suggesting that endogenous IL-10 blunted TNF-␣ pro- normalized by mean using the untreated sample as the baseline within each experiment. To identify differentially expressed genes, we excluded all duction. We concluded that a system devoid of endogenous IL-10 genes from the analysis that were scored absent in the test sample (for would be advantageous for uncovering the full spectrum of IL-10- up-regulated genes) or absent in the baseline sample (for down-regulated induced changes in gene expression.
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