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

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‐α and interferon‐γ release by NK cells, respectively. In contrast, endogenous transforming growth factor‐β1 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 β subunit utilized by IL‐15, it had no effect on the expression of the β1 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.