A comparative study of the effects of inhibitory cytokines on human natural killer cells and the mechanistic features of transforming growth factor-beta

Cell Immunol. 2014 Jul;290(1):52-61. doi: 10.1016/j.cellimm.2014.05.001. Epub 2014 May 13.

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).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / pharmacology
  • Cell Line
  • Cell Proliferation
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / pharmacology
  • Interleukin-2 / immunology
  • Interleukin-4 / immunology
  • Interleukin-4 / pharmacology
  • Intracellular Signaling Peptides and Proteins / immunology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / immunology
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Neoplasms / immunology*
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / immunology
  • Protein-Tyrosine Kinases / immunology
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Receptors, Androgen / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Syk Kinase
  • Transcription Factor AP-1 / genetics
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Escape / immunology*

Substances

  • AR protein, human
  • Anthracenes
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • IL10 protein, human
  • IL2 protein, human
  • IL4 protein, human
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Interleukin-10
  • pyrazolanthrone
  • Interleukin-4
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human