Abstract
The major factors and mechanisms by which natural killer (NK) cells are inhibited in cancer patients have not yet been well defined. In this study, we conducted a comparative analysis of the effects of TGF-β, IL-10, and IL-4 on primary NK cells, and it was demonstrated that (1) TGF-β most potently inhibited the overall function of NK cells. (2) It appears that TGF-β reduced the tyrosine phosphorylation of Syk and the expression of c-myc. (3) It was also found that the IL-2-induced promoter-binding activities of C-myb, AP-1, CREB, and AR were also completely suppressed upon TGF-β treatment. Interestingly, TGF-β also completely suppressed other transcription factors, which are constitutively activated. Among these factors, we further confirmed roles of AP-1 in NK-92 cell activation through c-jun and MEK1 inhibitor assay. Our study provides insight into the effects of TGF-β in modulating NK cell functions.
Keywords:
Immunosuppression; Interleukin-10 (IL-10); Interleukin-4 (IL-4); Natural killer (NK) cell; Signaling; Transcription regulation; Transforming growth factor beta (TGF-β).
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Anthracenes / pharmacology
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Cell Line
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Cell Proliferation
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Cyclic AMP Response Element-Binding Protein / genetics
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Humans
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Interferon-gamma / biosynthesis
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Interferon-gamma / metabolism
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Interleukin-10 / immunology
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Interleukin-10 / pharmacology
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Interleukin-2 / immunology
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Interleukin-4 / immunology
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Interleukin-4 / pharmacology
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Intracellular Signaling Peptides and Proteins / immunology
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Lymphocyte Activation / immunology
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MAP Kinase Kinase 1 / antagonists & inhibitors
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Neoplasms / immunology*
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Phosphorylation / drug effects
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Promoter Regions, Genetic / immunology
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Protein-Tyrosine Kinases / immunology
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Proto-Oncogene Proteins c-myb / genetics
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Proto-Oncogene Proteins c-myc / biosynthesis
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Receptors, Androgen / genetics
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Syk Kinase
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Transcription Factor AP-1 / genetics
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Transforming Growth Factor beta / immunology*
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Transforming Growth Factor beta / pharmacology*
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Tumor Escape / immunology*
Substances
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AR protein, human
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Anthracenes
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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IL10 protein, human
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IL2 protein, human
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IL4 protein, human
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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MYC protein, human
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Proto-Oncogene Proteins c-myb
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Proto-Oncogene Proteins c-myc
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Receptors, Androgen
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Transcription Factor AP-1
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Transforming Growth Factor beta
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Interleukin-10
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pyrazolanthrone
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Interleukin-4
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Interferon-gamma
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human