IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway

Cell Immunol. 2006 Jul;242(1):39-45. doi: 10.1016/j.cellimm.2006.09.002. Epub 2006 Oct 27.


TGF-beta is known to play a major role for the reduced NKG2D expression seen in cancer patients. However, the mechanisms for reduced TGF-beta-induced down-regulation of NKG2D are unclear. In this study, we observed that IL-2/IL-18 increased the NKG2D expression in the TGF-beta treated NK cell line in a dose-dependent manner. Incubation with the JNK inhibitor SP600125 inhibited the NKG2D expression induced by IL-2/IL-18 in the TGF-beta treated human NK cell line. Moreover, the NK cytotoxicity assay showed that the reduced NK cytotoxicity by TGF-beta was recovered by IL-2/IL-18 treatment. The results indicate that IL-2/IL-18 strongly prevented the TGF-beta-induced NKG2D down-regulation in NK cells via the JNK pathway. Taken together, the protected expression of NKG2D by IL-2/IL-18 provides insight into the mechanism of NKG2D regulation and it also supplied useful information for creating a novel therapeutic approach to treat TGF-beta-secreting cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cytotoxicity, Immunologic
  • Down-Regulation
  • Flow Cytometry
  • Humans
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism*
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / immunology
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Signal Transduction / immunology
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*


  • Interleukin-18
  • Interleukin-2
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Transforming Growth Factor beta
  • JNK Mitogen-Activated Protein Kinases