Cytokines regulate the expression of specific sets of proteins which mediate their biological effects. We have comprehensively delineated the regulation of the human tryptophanyl-tRNA synthetase (hWRS) by eight different cytokines (including IFNs) and poly(I).poly(C) in several cell lines. Six non-lymphoid cell lines were tested, and all of these produced human, IFN inducible hWRS (gamma 2) mRNA upon stimulation with IFN-gamma. In all these cell lines the level of gamma 2 mRNA increased 2-4 h after induction reaching a stable plateau after 8-12 h. The IFN-gamma induction of gamma 2 mRNA could be blocked by cycloheximide in human amniotic (AMA) cells, epithelial HeLa cells and HT1080 fibroblasts, but not in T98G glioblastoma cells. IFN-alpha and poly(I).poly(C) elicited small, transient gamma 2 responses in a few of the non-lymphoid cell lines, whereas none of the other six cytokines tested elicited a response. The six lymphoid cell lines tested did not show the same induction pattern. In the monocytic cells, THP-1, gamma 2 mRNA was highly induced by IFN-gamma, whereas in the B-cell line, Daudi, gamma 2 mRNA was transiently induced by IFN-alpha and poly(I).poly(C), and not by IFN-gamma. Altered mRNA turnover rate as a consequence of IFN-gamma treatment did not appear to play a significant role in the accumulation of gamma 2 transcript, since the stability essentially was the same in induced versus non-induced cells. We conclude that the hWRS gene is induced preferentially by IFN-gamma, and that the induction pattern resembles the one reported for the IFN induced enzyme, indoleamine 2,3-dioxygenase (IDO).