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IL-2 and IL-12 Alter NK Cell Responsiveness to IFN- Γ-Inducible Protein 10 by Down-Regulating CXCR3 Expression

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IL-2 and IL-12 Alter NK Cell Responsiveness to IFN- Γ-Inducible Protein 10 by Down-Regulating CXCR3 Expression IL-2 and IL-12 Alter NK Cell Responsiveness to IFN- γ-Inducible Protein 10 by Down-Regulating CXCR3 Expression This information is current as Deborah L. Hodge, William B. Schill, Ji Ming Wang, Isaac of September 29, 2021. Blanca, Della A. Reynolds, John R. Ortaldo and Howard A. Young J Immunol 2002; 168:6090-6098; ; doi: 10.4049/jimmunol.168.12.6090 http://www.jimmunol.org/content/168/12/6090 Downloaded from References This article cites 37 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/168/12/6090.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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-2 and IL-12 Alter NK Cell Responsiveness to IFN-␥-Inducible Protein 10 by Down-Regulating CXCR3 Expression1 Deborah L. Hodge,* William B. Schill,‡ Ji Ming Wang,† Isaac Blanca,* Della A. Reynolds,* John R. Ortaldo,* and Howard A. Young2* Cytokine treatment of NK cells results in alterations in multiple cellular responses that include cytotoxicity, cytokine production, proliferation, and chemotaxis. To understand the molecular mechanisms underlying these responses, microarray analysis was performed and the resulting gene expression patterns were compared between unstimulated, IL-2, IL-2 plus IL-12, and IL-2 plus IL-18-stimulated NK92 cells. RNase protection assays and RT-PCR confirmed microarray predictions for changes in mRNA expression for nine genes involved in cell cycle progression, signal transduction, transcriptional activation, and chemotaxis. Multiprobe RNase protection assay also detected changes in the expression of CCR2 mRNA, a gene that was not imprinted on the microarray. We subsequently expanded our search for other chemokine receptor genes absent from the microarray and found an Downloaded from IL-2- and IL-12-dependent decrease in CXCR3 receptor mRNA expression in NK92 cells. A detailed analysis of CXCR3 expres- sion in primary NK cells revealed that an IL-2 and an IL-12 together significantly decreased the CXCR3 receptor mRNA and receptor surface expression by 6 and 24 h of treatment, respectively. This decrease in receptor expression was associated with a significant reduction in chemotaxis in the presence of IFN-␥-inducible protein-10. The decline in CXCR3 mRNA was due to transcriptional and posttranscriptional mechanisms as the addition of actinomycin D to IL-2- and IL-12-treated NK92 slightly altered the half-life of the CXCR3 mRNA. Collectively, these data suggest that IL-2 and IL-12 directly affect NK cell migratory http://www.jimmunol.org/ ability by rapid and direct down-regulation of chemokine receptor mRNA expression. The Journal of Immunology, 2002, 168: 6090–6098. atural killer (NK) cells are large granular lymphocytes predicting patterns of gene expression in tumor cells (7, 8). To that play an important role in the defense against virally examine gene expression in response to cytokine stimulation, a N infected or malignant cells (1). Their activity can be human NK cell line, NK92, was stimulated with IL-2 alone or in characterized as nonadaptive and independent of MHC restriction combination with IL-12 or IL-18. These cytokines were chosen (1, 2). A variety of NK cell functions including cytotoxicity, pro- because of their ability to induce NK cell responses; however, little by guest on September 29, 2021 liferation, chemotaxis, and cytokine production are modulated by is known about the repertoire of genes that are activated by these regulatory cytokines including IFN-␣␤, IL-2, IL-12, IL-18, IL-10, cytokines. Microarray analysis of gene expression in NK92 cells and TNF (reviewed in Refs. 3 and 4). Because cytokines induce identified a variety of genes whose mRNA expression patterns such a broad range of effects in NK cells, the potential for alter- change in response to cytokine stimulation. The genes encoding ations in gene expression in stimulated cells is very great. To de- the mRNAs are not specific to any one pathway; however, changes termine which genes are regulated in response to cytokine stimu- in cytokine, chemokine, and chemokine receptor gene mRNAs lation, our laboratory has used cDNA microarray technology to were prevalent. Our mRNA studies on chemokine receptor gene examine gene expression in NK cells. Microarray technology is expression were extended to cell surface analysis of receptor den- very useful because it allows for large-scale examination of gene sities in cytokine-treated primary NK cells. Using FACS analysis, expression. Additionally, this technology has proved useful in we observed a significant decrease in CXCR3 receptor expression identifying physiologically relevant gene expression patterns in in NK cells treated for 24 h with IL-2 and IL-12 alone or in com- eukaryotic systems such as yeast (5) and fibroblasts (6) as well as bination. Recently, alterations in chemokine receptor expression were reported in IL-2-stimulated NK cells (9); however, the cells were cultured in IL-2 for 8–10 days. In contrast, our data demon- Laboratories of *Experimental Immunology and †Molecular Immunoregulation, Cen- strate that cytokines can modify chemokine receptor function ter for Cancer Research, National Cancer Institute, Frederick, MD 21702; and ‡Na- tional Fish Health Research Laboratory, U.S. Geological Survey-Leetown Science within hours, thus supporting a model whereby cytokines, in par- Center, Kearneysville, WV 25430 ticular IL-2 and IL-12, regulate chemokine receptor expression in Received for publication September 14, 2001. Accepted for publication April 5, 2002. a direct, rapid, and novel manner. 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 with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods 1 This project has been funded in whole or in part with Federal funds from the Na- NK cell preparation tional Cancer Institute, National Institutes of Health under Contract No. N01-CO- 12400. The publisher or recipient acknowledges the right of the U. S. Government to PBMC were isolated from buffy coats of healthy donors (obtained from the retain a nonexclusive, royalty-free license in and to copyright covering the article. The National Institutes of Health Blood Bank, Bethesda, MD) after centrifu- content of this publication does not necessarily reflect the views or policies of the gation on a lymphocyte separation medium. Cells were washed twice with Department of Health and Human Services, nor does mention of trade names, com- Dulbecco’s PBS and suspended in RPMI 1640 medium supplemented with mercial products, or organizations imply endorsement by the U. S. Government. 2mML-glutamine, 100 IU/ml penicillin, 50 ␮g/ml streptomycin, and 10% 2 Address correspondence and reprint requests to Dr. Howard A. Young, National FCS. Adherent cells were removed by incubation in plastic flasks for 1 h Cancer Institute, Building 560, Room 31-23, Frederick, MD 21702-1201. E-mail at 37°C. Nonadherent cells were recovered by gently washing with warmed address: [email protected] medium and were further purified by incubating on nylon wool columns for Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 6091 1 h at 37°C. The nylon-nonadherent cells (mostly T cells and NK cells) Ϫ70°C for 30 min, and subjected to centrifugation at 14,000 rpm for 15 were eluted with prewarmed RPMI-640 medium and fractionated on a min in a room temperature microcentrifuge. The supernatants were de- seven-step Percoll gradient as previously described (10). The NK cell- canted, a sterile cotton swap was used to remove excess liquid, and the enriched low-density fraction-2 (40–60% NK cells) was further depleted pellet was resuspended in 3 ␮l of BD PharMingen sample buffer. Each of remaining T lymphocytes and monocytes by negative selection with multiprobe RNase assay included probes specific for ribosomal L32 and anti-CD3 and anti-CD14 mAbs. Briefly, the cells were labeled for 30 min GAPDH mRNAs to assure equal amounts of input mRNA in each assay on ice with biotinylated anti-CD3 and anti-CD14 Abs. After removing the and to control for lane to lane variation during PAGE. unbound Abs by washing with cold PBS plus 1% BSA, the cells were For guanylate binding protein 1 (GBP-1)-1 and Src homology 2 domain- incubated 15 min with streptavidin microbeads (Miltenyi Biotec, Oslo, containing leukocyte protein of 76 kD (SLP-76) mRNA analysis, RPA Norway) and the positive cells (CD3ϩ and CD14ϩ) were removed with a probes were synthesized from plasmid DNA templates using T7 RNA magnetic column (MACS; Miltenyi Biotec). Purified NK cell populations polymerase and [␣-33P]UTP in an in vitro transcription reaction. The newly were Ͼ95% CD56ϩ/CD5Ϫ cells as determined by two-color flow cytom- synthesized riboprobes were loaded onto a 6% denaturing polyacrylamide etry analysis (FACSort; BD Biosciences, San Jose, CA) with anti-CD56 PE gel and full-length probes were excised and eluted from the gel by over- and anti-CD5 FITC (BD Biosciences).
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