Natural killer cell-produced IFN-γ and TNF-α induce target cell cytolysis through up-regulation of ICAM-1

J Leukoc Biol. 2012 Feb;91(2):299-309. doi: 10.1189/jlb.0611308. Epub 2011 Nov 1.


NK cells control tumor and virus-infected cells through releasing cytotoxic granules and proinflammatory cytokines. IFN-γ and TNF-α secretions and cytotoxicity are regarded as two distinct functions of NK cells with little synergy in between as results of early association of the two functions with distinct subsets of NK populations and of the studies showing target cells developing NK resistance upon IFN-γ treatment. Here, we show that IFN-γ and TNF-α synergistically enhance NK cell cytotoxicity through NF-κB-dependent up-regulation of ICAM-1 expression in target cells, thereby promoting their conjugate formation with NK cells. Neutralizing IFN-γ and TNF-α during cytolysis significantly impaired NK cell lysis of the target cells. Further, tumor cells exhibiting IFN-γ-inducible lysis are generally less-sensitive NK target cells but express inducible levels of ICAM-1. In contrast, sensitive NK targets tend to express higher but less-inducible ICAM-1. Their preferential induction in the lysis of insensitive NK target cells suggests that IFN-γ and TNF-α are functionally linked to and should be regarded as an integral part of NK cytolytic function.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • B7 Antigens / biosynthesis
  • B7 Antigens / genetics
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / physiology*
  • Drug Synergism
  • GPI-Linked Proteins / biosynthesis
  • GPI-Linked Proteins / genetics
  • Gene Expression Regulation
  • HLA Antigens / biosynthesis
  • HLA Antigens / genetics
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • NF-kappa B / metabolism
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*
  • Up-Regulation


  • B7 Antigens
  • GPI-Linked Proteins
  • HLA Antigens
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • NCR3LG1 protein, human
  • NF-kappa B
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • ULBP1 protein, human
  • ULBP2 protein, human
  • ULBP3 protein, human
  • Intercellular Adhesion Molecule-1
  • Interferon-gamma