Accessory functions of cellular adhesion molecules (CAM) in activation, adhesion, migration, and cytotoxicity of natural killer (NK) cells are partly dependent on activation by cytokines. We studied effects of interleukin 12 (IL12) on expression and function of adhesion molecules on human NK cells and compared them to the effects mediated by IL2. Target binding of NK cells was significantly increased by IL12, leading to an increased level of conjugate formation with K562 target cells as well as enhanced binding to tumor monolayers. IL12 also induced significant levels of cytotoxicity against fresh tumor cell targets in purified human NK cells. IL12 significantly enhanced adhesion and subsequent migration of NK cells through 3-microns-pore-size polycarbonate filters. However, IL2 was a more potent activator of these functions, which have been shown to be partly mediated by CD2, CD58, beta 2 integrins, and ICAM-1. As assessed by flow cytometry, IL12 also induced significant up-regulation in the proportion or mean fluorescence intensity of NK cells positive for the following activation markers and adhesion molecules: CD25, HLA-DR, CD69, CD71, CD56, CD2, and CD54. Among the beta 2 integrins, IL12 selectively increased expression of CD11a on NK cells, although to a significantly lower level than that induced by IL2. IL12 had different in vitro effects than IL2 on expression and function of the beta 1 integrins. Whereas IL2 induced marked up-regulation in expression of the beta 1 integrins, CD49b, -c, -d, and -e, IL12 had no demonstrable effect over a wide range of concentrations. In addition, while IL2-activated NK cells showed significantly increased integrin-dependent adhesion to fibronectin- or laminin-coated plates, IL12-activated cells were less adherent to fibronectin and were unchanged in their adherence to laminin. Our data demonstrate that IL12 is involved in interactions of NK cells with fresh or cultured tumor cell targets, biologic substrates, or extracellular matrix molecules. Although the magnitude of its in vitro effects on adhesion-dependent functions of NK cells was significantly smaller than that of IL2, lower doses of IL12 were required to up-regulate functions of CAM, and this may be an attractive feature of IL12 as a potential therapeutic cytokine.