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IL-13 System by Β Regulation of the Monocyte IL-1 Transcriptional

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IL-13 System by Β Regulation of the Monocyte IL-1 Transcriptional Transcriptional Profiling Reveals Complex Regulation of the Monocyte IL-1 β System by IL-13 This information is current as Chris J. Scotton, Fernando O. Martinez, Maaike J. Smelt, of September 29, 2021. Marina Sironi, Massimo Locati, Alberto Mantovani and Silvano Sozzani J Immunol 2005; 174:834-845; ; doi: 10.4049/jimmunol.174.2.834 http://www.jimmunol.org/content/174/2/834 Downloaded from References This article cites 74 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/174/2/834.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 29, 2021 *average 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Transcriptional Profiling Reveals Complex Regulation of the Monocyte IL-1␤ System by IL-131 Chris J. Scotton,2* Fernando O. Martinez,*† Maaike J. Smelt,* Marina Sironi,* Massimo Locati,† Alberto Mantovani,*† and Silvano Sozzani3*‡ IL-4 and IL-13 are prototypic Th2 cytokines that generate an “alternatively activated” phenotype in macrophages. We used high-density oligonucleotide microarrays to investigate the transcriptional profile induced in human monocytes by IL-13. After 8-h stimulation with IL-13, 142 genes were regulated (85 increased and 57 decreased). The majority of these genes were related to the inflammatory response and innate immunity; a group of genes related to lipid metabolism was also identified, with clear impli- cations for atherosclerosis. In addition to characteristic markers of alternatively activated macrophages, a number of novel IL-13-regulated genes were seen. These included various pattern recognition receptors, such as CD1b/c/e, TLR1, and C-type lectin superfamily member 6. Several components of the IL-1 system were regulated. IL-1RI, IL-1RII, and IL-1Ra were all up-regulated, Downloaded from whereas the IL-1␤-converting enzyme, caspase 1, and IRAK-M were down-regulated. LPS-inducible caspase 1 enzyme activity was also reduced in IL-13-stimulated monocytes, with a consequent decrease in pro-IL-1␤ processing. These data reveal that IL-13 has a potent effect on the transcriptional profile in monocytes. The IL-13-induced modulation of genes related to IL-1 clearly highlights the tightly controlled and complex levels of regulation of the production and response to this potent proinflammatory cytokine. The Journal of Immunology, 2005, 174: 834–845. http://www.jimmunol.org/ onocytes and macrophages (M␾)4 play a central role TNF-␣, IL-12, IL-6, and CCL2; they up-regulate expression of Ϫ in both innate and adaptive immunity. They constitute MHC class II and CD86, and they produce NO and O2 (3, 5–7). M a nonspecific first line of defense by phagocytosing These cells are particularly important for killing and degrading opsonized or nonopsonized microorganisms; they can also act as intracellular pathogens. APCs, thereby stimulating a specific immune response. Monocytes Type 2-activated M␾ arise from Fc␥R ligation followed by ϩ are derived from CD34 myeloid progenitor cells in the bone mar- stimulation of TLR, CD40 or CD44. These cells produce many of row, and subsequently leave the bone marrow to circulate in the the cytokines seen in classically activated M␾ (e.g., TNF-␣ and bloodstream (1). Inflammation due to tissue damage or infection IL-6), but they switch off IL-12 production and secrete large quan- by guest on September 29, 2021 results in the production of cytokines, chemokines, and other in- tities of IL-10 (8–10). These cells therefore exert a potent anti- flammatory mediators, which can influence monocyte function, inflammatory effect, and because IL-10 can stimulate IL-4 produc- causing recruitment to the site of inflammation and differentiation tion by T cells, they also preferentially induce a Th2 response (11). ␾ ␾ into M . Different subpopulations of activated M exist, depend- In contrast, alternatively activated M␾ are induced by IL-4, IL- ␾ ing on the type of stimulus they receive. M are currently divided 13, or glucocorticoids. They secrete IL-10 and IL-1Ra and have into “classically activated,” “type 2-activated,” and “alternatively increased expression of scavenger receptor and mannose receptor, activated” populations (see Refs. 2–4 for recent review). but they are poor producers of reactive oxygen species or NO (3). ␾ ␥ In classical activation, exposure of M to IFN- primes the cells Thus, these cells are unable to efficiently kill intracellular patho- ␣ to respond to further stimulation by TNF- or an inducer of gens. The up-regulation of mannose receptor (12) may increase the ␣ TNF- , frequently LPS or other bacterially derived products. potential for alternatively activated M␾ to present Ag, as has been These cells secrete various cytokines and chemokines including shown for dendritic cells (DC) (13, 14), but these M␾ can also inhibit the proliferation of T cells under certain circumstances (15). *Istituto di Ricerche Farmacologiche Mario Negri, and †Section of General Pathol- Various cell types produce IL-4 and IL-13, including Th2 cells, ogy, University of Milan, Milan, Italy; and ‡Section of General Pathology and Im- mast cells, and basophils; they play an important role in Th2 in- munology, University of Brescia, Brescia, Italy flammation, particularly in the pathogenesis of allergy, asthma, Received for publication May 4, 2004. Accepted for publication October 14, 2004. atopic dermatitis, and also inhibition of certain forms of autoim- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance munity (2). They have a similar three-dimensional structure and with 18 U.S.C. Section 1734 solely to indicate this fact. share receptor complexes (16). As a result, these two cytokines 1 C.J.S. was supported by a Marie Curie Fellowship from the European Community signal through common components; IL-13 binding causes activa- Human Potential Programme under Contract No. HPMF-CT-2001-01410. We also tion of JAK1 and Tyk2, which in turn causes phosphorylation of thank Associazione Italiana per la Ricerca sul Cancro and Ministero dell’Istruzione ␣ Universita`e Ricerca (cofin 2002) for financial support. cytoplasmic tyrosines in the IL-4R chain. Crucially, this allows 2 Current address: Centre for Respiratory Research, University College London, the recruitment of STAT6 to the receptor and subsequent phos- Rayne Institute, London, U.K. phorylation/activation; STAT6 can then dimerize, translocate to 3 Address correspondence and reprint requests to Dr. Silvano Sozzani, Section of the nucleus, and activate transcription of target genes (see Hershey General Pathology and Immunology, University of Brescia, viale Europa 11, 25123 (17) for comprehensive review). IL-4 and IL-13 therefore have Brescia, Italy. E-mail address: [email protected] overlapping but pleiotropic functions, which include enhancing B 4 Abbreviations used in this paper: M␾, macrophage; TF, transcription factor; Ct, cycle threshold; DC, dendritic cell; GO, Gene Ontology; EASE, Expression Analysis cell proliferation and isotype-switching, antagonizing the effects of Systematic Explorer; FLICA, fluorochrome inhibitor of caspases. IFN-␥, inducing the differentiation of DC (in combination with Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 835 GM-CSF), and affecting T cell proliferation and differentiation (for Efficiency RNA Transcript Labeling kit (Enzo Life Sciences), cleaned up IL-4, but not IL-13). They can also act on nonhemopoietic cells, using the Qiagen RNeasy Mini Kit and ethanol precipitation, and frag- including endothelial cells and smooth muscle cells where IL-13 mented, before microarray analysis. stimulation enhances the production of CXCL8, CCL2, and Affymetrix genechip analysis and data mining CCL5 (18, 19). To elucidate the effects of IL-13 in the early stages of the dif- Fragmented cRNA was hybridized to Affymetrix HG-U133A genechips ␾ (Affymetrix), and then washed and scanned, according to the manufactur- ferentiation pathway to an alternatively activated M phenotype, er’s guidelines. These genechips contain 22,283 probe sets, corresponding freshly isolated human monocytes were stimulated with IL-13, and to almost 15,000 genes. Monocytes from six individual donors were ana- their transcriptional profile was investigated using high-density lyzed after 8-h incubation in the presence or absence of IL-13 (20 ng/ml). oligonucleotide microarray analysis. Monocytes from three of these donors were also analyzed after 2-h stim- Validation of this analysis was provided by the identification of ulation with IL-13. To define the IL-13-dependent transcriptional profile, expression measures were computed using robust multiarray average
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