IL-2 has pleiotropic properties and is a potent activator of monocytic functions. Since monocytes are an important source of the chemoattractant cytokine IL-8, we studied the effects of IL-2 on the expression of IL-8 in human monocytes. IL-8 mRNA expression was detectable in resting human monocytes. Treatment of monocytes with IL-2 increased IL-8 mRNA expression by a protein synthesis-independent process. The augmentation of IL-8 mRNA by IL-2 was associated with an increase in IL-8 secretion. The expression of IL-8 mRNA was not a nonspecific response to any stimulus of monocyte activation. In fact, IFN-gamma, which is also a potent monocyte activator, not only failed to induce IL-8 expression but inhibited the stimulation of IL-8 by IL-2. Nuclear run-on experiments demonstrated that both the enhancement of IL-8 mRNA expression and its down-regulation by IFN-gamma occurred at the transcriptional level. These results show for the first time that in fresh human monocytes, IL-8 expression is differentially regulated by IL-2 and IFN-gamma and suggest that the interactions among IL-2, IL-8, and IFN-gamma may be important for the development and control of the inflammatory response.