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4832.Full.Pdf IFN-α-Induced Signal Transduction, Gene Expression, and Antitumor Activity of Immune Effector Cells Are Negatively Regulated by Suppressor of Cytokine This information is current as Signaling Proteins of September 24, 2021. Jason M. Zimmerer, Gregory B. Lesinski, Sri Vidya Kondadasula, Volodymyr I. Karpa, Amy Lehman, Abhik RayChaudhury, Brian Becknell and William E. Carson III J Immunol 2007; 178:4832-4845; ; Downloaded from doi: 10.4049/jimmunol.178.8.4832 http://www.jimmunol.org/content/178/8/4832 http://www.jimmunol.org/ References This article cites 65 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/178/8/4832.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN-␣-Induced Signal Transduction, Gene Expression, and Antitumor Activity of Immune Effector Cells Are Negatively Regulated by Suppressor of Cytokine Signaling Proteins1 Jason M. Zimmerer,*† Gregory B. Lesinski,† Sri Vidya Kondadasula,† Volodymyr I. Karpa,† Amy Lehman,‡ Abhik RayChaudhury,§ Brian Becknell,† and William E. Carson III2†¶ Proteins belonging to the suppressors of cytokine signaling (SOCS) family have been shown to regulate cytokine signal trans- duction in various cell types but their role in modulating the response of immune cells to IFN-␣ has not been fully explored. We hypothesized that SOCS proteins would inhibit the antitumor activity of IFN-␣-stimulated immune cells. Transcripts for SOCS1, SOCS2, SOCS3, and cytokine-inducible Src homology 2-containing protein were identified in total human PBMC (PBMCs, NK 3 5 cells, and T cells) within 1–2 h of stimulation with IFN-␣ (10 –10 U/ml). Immunoblot analysis confirmed the expression of these Downloaded from factors at the protein level. Transcripts for SOCS proteins were rapidly but variably induced in PBMCs from patients with metastatic melanoma following the i.v. administration of IFN-␣-2b (20 million units/m2). Overexpression of SOCS1 and SOCS3, but not SOCS2, in the Jurkat T cell line inhibited IFN-␣-induced phosphorylated STAT1 and the transcription of IFN-stimulated genes. Conversely, small inhibitory RNA-mediated down-regulation of SOCS1 and SOCS3 in Jurkat cells and normal T cells enhanced the transcriptional response to IFN-␣. Loss of SOCS1 or SOCS3 in murine immune effectors was associated with enhanced IFN-induced phosphorylated STAT1, transcription of IFN-stimulated genes, and antitumor activity. Of note, IFN-␣ http://www.jimmunol.org/ treatment eliminated melanoma tumors in 70% of SOCS1-deficient mice, whereas IFN-treated SOCS-competent mice all died. The .antitumor effects of IFN-␣ in tumor-bearing SOCS1-deficient mice were markedly inhibited following depletion of CD8؉ T cells These results indicate that the antitumor response of immune effector cells to exogenous IFN-␣ is regulated by SOCS proteins. The Journal of Immunology, 2007, 178: 4832–4845. ecombinant IFN-␣ is used to treat patients with meta- The receptor for IFN-␣ is widely expressed on both tumor cells static malignant melanoma and is associated with an and immune effector cells (8, 12). Binding of IFN-␣ to its receptor overall response rate of 10–15% (1–3). High-dose IFN-␣ activates Jak1 and tyrosine kinase 2, which in turn phosphorylate R by guest on September 24, 2021 is also used as an adjuvant in patients who have undergone resec- tyrosine residues within the cytoplasmic region of the receptor. tion of high-risk lesions (nodal disease or primary tumors of These phosphotyrosine residues provide docking sites for STAT1 Breslow thickness Ͼ4 mm) (1, 3–6). However, it has been difficult and STAT2, latent cytoplasmic transcription factors that are phos- to determine the optimal dose of IFN-␣ for melanoma patients or phorylated by the Jaks (13). The prototypical IFN-␣-signaling re- devise strategies to enhance the antitumor effects of IFN-␣ because action results in the formation of IFN-stimulated gene factor 3, a its cellular targets and mechanism of action are largely unknown. DNA-binding complex that consists of STAT1␣ (or STAT1␤), Although exogenous administration of IFN-␣ can act directly on STAT2, and IFN regulatory factor 9 (14). IFN-stimulated gene melanoma cells to inhibit proliferation and up-regulate the expression factor 3 subsequently translocates to the nucleus and binds to IFN- of MHC class I Ags, its stimulatory properties on effector cells of the stimulated response elements located in the promoter regions of immune system are thought to be critical for its antitumor activity IFN-responsive genes (15). These signaling events induce the ex- (7–10). Dunn et al. (11) have also shown that endogenously produced pression of a variety of immunoregulatory genes and largely de- IFN-␣ is required for the prevention of carcinogen-induced tumors termine the pattern of immune cell activation following exposure and that host immune effector cells are critical targets of IFN-␣ during to IFN-␣ (9, 16–19). We have previously demonstrated a high the development of protective antitumor responses. degree of variability in the formation of phosphorylated STAT1 (P-STAT1)3 in patient immune effector cells following IFN-␣-2b immunotherapy and have shown that Jak-STAT signal transduc- *Integrated Biomedical Sciences Graduate Program, †Human Cancer Genetics Pro- tion is down-regulated at higher dose levels of IFN-␣ (20). These gram, Department of Molecular Virology, Immunology, and Medical Genetics, ‡Cen- data suggested that negative regulatory pathways might influence ter for Biostatistics, §Department of Pathology, ¶Department of Surgery, The Ohio State University, Columbus, OH 43210 signal transduction and gene expression in human immune cells following exposure to IFN-␣. Received for publication August 31, 2006. Accepted for publication January 30, 2007. Investigators have identified a family of proteins termed sup- 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 pressors of cytokine signaling (SOCS) that negatively regulate with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a seed grant from the Immunology Program of The 3 Abbreviations used in this paper: P-STAT1, phosphorylated STAT1; SOCS, sup- Ohio State University-Comprehensive Cancer Center and the Harry J. Lloyd Chari- pressor of cytokine signaling; SH2, Src homology 2; CIS, cytokine-inducible SH2- table Trust (to G.B.L.) and National Institutes of Health Grants P01 CA95426, K24 containing protein; ISG, IFN-stimulated gene; siRNA, small inhibitory RNA; hu, CA93670 (to W.E.C.), and P30 CA16058. human; EGFP, enhanced GFP; DC, dendritic cell; GH, growth hormone; MU, million 2 Address correspondence and reprint requests to Dr. William E. Carson III, Depart- units. ment of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. E-mail address: [email protected] Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org The Journal of Immunology 4833 Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021 FIGURE 1. SOCS transcripts are rapidly induced in PBMCs following IFN-␣ stimulation. PBMCs from normal donors were treated with IFN-␣ (103–105 U/ml) or PBS and SOCS mRNA levels were measured by real-time PCR at four time points (0.5, 1, 2, 4 h) using primers specific for (A) SOCS1, (B) SOCS2,(C) SOCS3,or(D) CIS. Data were expressed as the mean fold increase relative to baseline levels (PBS treatment). All real-time PCR data were normalized to the level of ␤-actin mRNA (housekeeping gene). E, Phosphorylation of STAT1 at Tyr701 was measured in parallel by flow cytometry. Mean-specific fluorescence (Fsp) is illustrated on the y-axis. Appropriate isotype control Abs were used to determine background staining. All flow cytometric data were derived from at least 10,000 events gated on the lymphocyte populations determined by light scatter properties (forward scattervs .Statistically significant results vs PBS treatment ,ء .(side scatter). Error bars denote the 95% confidence interval of triplicate experiments (three donors PBMCs were isolated from normal donors, stimulated with IFN-␣ (104 U/ml), and harvested at various times (1, 3, 5, 7, 24 h). Following immunopre- cipitation, SOCS protein levels were measured by immunoprecipitation and subsequent immunoblot analysis using Abs directed against (F) SOCS1, SOCS2, SOCS3, or CIS. Lysates from a SOCS-overexpressing human melanoma cell line (HT144) were used as positive controls. Due to the immuno- precipitation protocol, levels of ␤-actin were measured separately to control for loading. Densitometric
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