Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4

Eur J Immunol. 1996 Nov;26(11):2736-41. doi: 10.1002/eji.1830261128.


The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.

Publication types

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

MeSH terms

  • Blotting, Northern
  • Cytotoxicity, Immunologic / drug effects*
  • Granzymes
  • Humans
  • Interferon-gamma / drug effects
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-12 / pharmacology*
  • Interleukin-15 / metabolism
  • Interleukin-15 / pharmacology*
  • Interleukin-4 / pharmacology*
  • Killer Cells, Lymphokine-Activated / drug effects
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / drug effects*
  • Receptors, Interleukin / drug effects
  • Receptors, Interleukin-12
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2 / drug effects
  • Serine Endopeptidases / drug effects
  • Transforming Growth Factor beta / drug effects
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism


  • IL15RA protein, human
  • Interleukin-15
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases