title: Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4.
abstract: 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.
authors.affiliation: Laboratoire Cytokines et Immunité Antitumorale, Institut Gustave-Roussy, Villejuif, France.
authors.forename: O
authors.initials: O
authors.lastname: Salvucci
authors.forename: F
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: J L
authors.initials: JL
authors.lastname: Moreau
authors.forename: J
authors.initials: J
authors.lastname: Thèze
authors.forename: J
authors.initials: J
authors.lastname: Chehimi
authors.forename: S
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D015152:Blotting, Northern; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D018123:Receptors, Interleukin / Q000187:drug effects; D053707:Receptors, Interleukin-12; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D012697:Serine Endopeptidases / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: C508024:IL15RA protein, human; D019409:Interleukin-15; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases