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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, III^2,,¶

^* Integrated Biomedical Sciences Graduate Program, Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Center for Biostatistics, Department of Pathology, ^¶ Department of Surgery, The Ohio State University, Columbus, OH 43210

Proteins belonging to the suppressors of cytokine signaling (SOCS) family have been shown to regulate cytokine signal transduction 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 cells, and T cells) within 1–2 h of stimulation with IFN- (10³–10⁵ U/ml). Immunoblot analysis confirmed the expression of these 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- 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 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.

¹ This work was supported by a seed grant from the Immunology Program of The Ohio State University-Comprehensive Cancer Center and the Harry J. Lloyd Charitable Trust (to G.B.L.) and National Institutes of Health Grants P01 CA95426, K24 CA93670 (to W.E.C.), and P30 CA16058.

² Address correspondence and reprint requests to Dr. William E. Carson III, Department of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. E-mail address: William.carson{at}osumc.edu

³ Abbreviations used in this paper: P-STAT1, phosphorylated STAT1; SOCS, suppressor of cytokine signaling; SH2, Src homology 2; CIS, cytokine-inducible SH2-containing protein; ISG, IFN-stimulated gene; siRNA, small inhibitory RNA; hu, human; EGFP, enhanced GFP; DC, dendritic cell; GH, growth hormone; MU, million units.

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