The Cytokine Profile of Resting and Activated NK Cells

The evidence accumulated in the past few years has indicated that natural killer (NK) cells, originally identified on the basis of their ability to mediate spontaneous cytotoxicity, play a primary role in regulating immune responses and homeostasis via release of cytokines. Polyclonal populations of NK cells can be induced to produce an overlapping set of soluble factors. Some of these, represented primarily by IFN-gamma, TNF-alpha, and several growth factors for hematopoietic cells, have been clearly identified; others may represent novel cytokines. Production of specific cytokine subsets by distinct NK-cell subpopulations has not been documented, and the same cytokines are produced, in response to distinct stimuli, by both resting and activated NK cells, with the differences being for the most part quantitative, rather than qualitative. No cytokines capable of regulating NK-cell proliferation in an autocrine fashion have been described, and, with the exception of IL-5, cytokine production is not correlated with the proliferative capability of the cells. In this review, the stimuli leading to cytokine production are discussed in light of the knowledge of the molecular mechanisms by which distinct ligands (target cells, ligands for specific receptors, antibodies to triggering molecules, cytokines) regulate expression of cytokine-encoding genes and variably modulate each others' effects. The biological consequences of the production of specific cytokines are related to their effects on the NK cells themselves and on other hematopoietic and nonhematopoietic cell types. These are discussed, in an attempt to provide a picture that helps in understanding how NK cells may participate in regulating inflammatory and immune responses independently, at least in part, of their cytotoxic functions.