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As a New Hypoxia-Inducible Gene of October 1, 2021 Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 This information is current as as a New Hypoxia-Inducible Gene of October 1, 2021. Maria Carla Bosco, Maura Puppo, Clara Santangelo, Luca Anfosso, Ulrich Pfeffer, Paolo Fardin, Florinda Battaglia and Luigi Varesio J Immunol 2006; 177:1941-1955; ; Downloaded from doi: 10.4049/jimmunol.177.3.1941 http://www.jimmunol.org/content/177/3/1941 References This article cites 81 articles, 27 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/177/3/1941.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene1 Maria Carla Bosco,2* Maura Puppo,* Clara Santangelo,* Luca Anfosso,‡ Ulrich Pfeffer,† Paolo Fardin,* Florinda Battaglia,* and Luigi Varesio* Peripheral blood monocytes migrate to and accumulate in hypoxic areas of inflammatory and tumor lesions. To characterize the molecular bases underlying monocyte functions within a hypoxic microenvironment, we investigated the transcriptional profile induced by hypoxia in primary human monocytes using high-density oligonucleotide microarrays. Profound changes in the gene expression pattern were detected following 16 h exposure to 1% O2, with 536 and 677 sequences showing at least a 1.5-fold increase and decrease, respectively. Validation of this analysis was provided by quantitative RT-PCR confirmation of expression differences Downloaded from of selected genes. Among modulated genes, 74 were known hypoxia-responsive genes, whereas the majority were new genes whose responsiveness to hypoxia had not been previously described. The hypoxic transcriptome was characterized by the modulation of a significant cluster of genes with immunological relevance. These included scavenger receptors (CD163, STAB1, C1qR1, MSR1, MARCO, TLR7), immunoregulatory, costimulatory, and adhesion molecules (CD32, CD64, CD69, CD89, CMRF-35H, ITGB5, LAIR1, LIR9), chemokines/cytokines and receptors (CCL23, CCL15, CCL8, CCR1, CCR2, RDC1, IL-23A, IL-6ST). Furthermore, http://www.jimmunol.org/ we provided conclusive evidence of hypoxic induction of CCL20, a chemoattractant for immature dendritic cells, activated/memory T lymphocytes, and naive B cells. CCL20 mRNA up-regulation was paralleled by increased protein expression and secretion. This study represents the first transcriptome analysis of hypoxic primary human monocytes, which provides novel insights into mono- cyte functional behavior within ischemic/hypoxic tissues. CCL20 up-regulation by hypoxia may constitute an important mecha- nism to promote recruitment of specific leukocyte subsets at pathological sites and may have implications for the pathogenesis of chronic inflammatory diseases. The Journal of Immunology, 2006, 177: 1941–1955. eripheral blood monocytes (Mn)3 represent the early coupled receptors differentially expressed and regulated in leuko- mononuclear phagocyte component of the leukocyte infil- cytes (2). CCL20 (also known as MIP-3␣, liver and activation by guest on October 1, 2021 P trate at sites of inflammation, infection, and tumor growth, regulated chemokine, and Exodus) is a recently described Mn- where they differentiate into inflammatory and tumor-associated derived CC-chemokine which selectively attracts immature den- macrophages (Mf) (1). Mn/Mf are potent regulators of immune dritic cells (iDC), effector/memory T lymphocytes, and naive B and inflammatory reactions. They orchestrate the coordinated re- cells through its specific receptor, CCR6, expressed on these cells cruitment and activation of specific leukocyte subsets at patholog- (for a review, see Ref. 3). ical sites through the local secretion of low m.w. structurally re- Mononuclear phagocyte reactivity in pathological tissues is lated proteins, termed chemokines (1). Chemokines are classified finely tuned by a complex interplay between stimulatory and in- into CXC, CC, C, and CX3C families, which bind to and activate hibitory signals of various nature that include immune-derived members of a superfamily of 7-transmembrane domain, G protein- stimuli (4, 5), viral/bacterial products (5, 6), cell metabolites (4, 7), and tissue-specific signals (8). A common denominator of many pathological processes and an important regulator of gene expres- † *Laboratory of Molecular Biology, G. Gaslini Institute, and Functional Genomics, sion is represented by low partial oxygen pressure (pO ) (reviewed National Cancer Research Institute, Genova, Italy; and ‡University of Insubria, Va- 2 rese, Italy in Ref. 9). Hypoxia occurs in cardiovascular, hematological, and Received for publication November 4, 2005. Accepted for publication May 18, 2006. pulmonary disorders, ischemic wounds, arthritic joints, atheroscle- The costs of publication of this article were defrayed in part by the payment of page rotic plaques, and microbial infections, and experimental and clin- charges. This article must therefore be hereby marked advertisement in accordance ical studies point toward its fundamental role in the pathogenesis with 18 U.S.C. Section 1734 solely to indicate this fact. of these diseases (8–11). Areas of low pO2 are also present in solid 1 This work was supported by grants from the Italian Association for Cancer Re- tumors, where they have been associated with malignant progres- search, Fondazione Italiana per la Lotta al Neuroblastoma, San Paolo Company, Ital- ian Health Ministry, and Ministero Istruzione Universita’ e Ricerca. sion, metastasis formation, resistance to therapy, and poor clinical 2 Address correspondence and reprint requests to Dr. Maria Carla Bosco, Laboratorio outcome (8, 12–14). Transcriptional response to hypoxia is medi- di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, L.go Gerolamo ated primarily by the hypoxia-inducible factor-1 (HIF-1), a het- Gaslini 5, 16147 Genova Quarto, Italy. E-mail address: [email protected] erodimeric basic helix-loop-helix (bHLH) transcription factor 3 Abbreviations used in this paper: Mn, monocyte; Mf, macrophage; iDC, immature composed of HIF-1␤ (also known as the aryl hydrocarbon receptor dendritic cell; pO2, partial oxygen pressure; HIF-1, hypoxia-inducible factor-1; GO, Gene Ontology; EASE, Expression Analysis Systematic Explorer; qRT-PCR, real- nuclear translocator (ARNT)), the constitutive subunit, and HIF- time quantitative PCR; VEGF, vascular endothelial growth factor; HMG, hypoxia- 1␣,2␣,or3␣, the oxygen-sensitive subunits (9, 15). The ␣ sub- modulated gene; IRS, immunoregulatory signaling; ARNT, aryl hydrocarbon receptor nuclear translocator; ECM, extracellular matrix; hMDM, human monocyte-derived units are posttranslationally stabilized under hypoxia and translo- macrophage; MMP, matrix metalloproteinase; bHLH, basic helix-loop-helix. cate to the nucleus where they dimerize with HIF-1␤, Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 1942 TRANSCRIPTIONAL PROFILE OF HYPOXIC MONOCYTES transactivating the hypoxia responsive element present in the pro- conducted by electrophoresis with an Agilent Bioanalyzer 2100 (Agilent Technologies Europe). For each experimental condition, equal amounts of moter of many O2-sensitive genes (9, 15). Regulation of HIF-1 expression and activity by hypoxia is a tightly regulated process Mn RNA from 15 different donors were randomly pooled into three sub- sets, and the RNA pools were used for probe preparation. Briefly, 20 ␮gof which results from the activity of several oxygen-dependent en- RNA were reverse transcribed into double-stranded cDNA on a GeneAmp zymes and requires interaction and cooperation with various tran- PCR System 2700 thermal cycler (Applied Biosystems), using the Super- scriptional cofactors and other transcription factors (15). Script Double-Stranded cDNA Synthesis kit (Invitrogen Life Technolo- Mononuclear phagocytes accumulate preferentially in hypoxic/ gies) according to the manufacturer’s instructions, except that a T7-(dT)24 primer (high purity salt-free purified) was used in place of the oligo pro- ischemic areas of diseased tissues (1), and hypoxic conditions have vided with the kit. cDNA was purified and used for in vitro transcription been shown to profoundly affect their proinflammatory and immu- with the BioArray High Efficiency RNA Transcript Labeling kit (Enzo Life noregulatory responses by modulating the expression of genes Sciences) in the presence of biotin-11-CTP and biotin-16-UTP. Labeled coding for angiogenic factors, inflammatory
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