IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins.

IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Research Abstract Details 

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IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Abstract Text:

Jason M Zimmerer,Gregory B Lesinski,Sri Vidya Kondadasula,Volodymyr I Karpa,Amy Lehman,Abhik Raychaudhury,Brian Becknell,William E Carson,

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-alpha has not been fully explored. We hypothesized that SOCS proteins would inhibit the antitumor activity of IFN-alpha-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-alpha (10(3)-10(5) 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-alpha-2b (20 million units/m(2)). Overexpression of SOCS1 and SOCS3, but not SOCS2, in the Jurkat T cell line inhibited IFN-alpha-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-alpha. 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-alpha treatment eliminated melanoma tumors in 70% of SOCS1-deficient mice, whereas IFN-treated SOCS-competent mice all died. The antitumor effects of IFN-alpha 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-alpha is regulated by SOCS proteins.

IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Publishing Authors By Initials

JM Zimmerer,GB Lesinski,SV Kondadasula,VI Karpa,A Lehman,A Raychaudhury,B Becknell,WE Carson,

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IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of immunology (Baltimore, Md. : 1950)

VOLUME: 178

Page Numbers: 4832-45

Journal Abbreviation: J. Immunol.

ISSN: 0022-1767

DAY: 15

MONTH: Apr

YEAR: 2007

IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985117

IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Keywords Mesh Terms:

KEYWORDS: Suppressor of Cytokine Signaling Protein

MESH TERMS: physiology

Chemical & Substance for Abstract: IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. Information

Substance Name: cytokine inducible SH2-containing protei

Registry Number: 0

Grant and Affiliation Information for IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins.

AFFILIATION: Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA.

Country: United States

AGENCY: United States NCI

GRANT: P30 CA16058

ACRONYM: CA

MEDLINETA: J Immunol

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