The goal of this study was to determine whether cytokines modulate leukotriene C 4 (LTC 4) synthase expression in mononuclear phagocytes. A panel of cytokines was surveyed for changes in LTC 4 synthase mRNA in THP-1 cells. TGF-β1,-2, and-3 had significant stimulatory effects. The addition of TGF-β resulted in a time-dependent increase in LTC 4 synthase mRNA at 6 h, which persisted through 48 h. Furthermore, this conditioning resulted in an increase in immunoreactive protein for LTC 4 synthase through 7 days. TGF-β conditioning of cells resulted in a time-and dose-dependent increase in stimulated LTC 4 synthase activity. Following transient transfection of THP-1 cells with a promoter-reporter construct containing 1.2 kb of the LTC 4 synthase promoter, TGF-β treatment resulted in a 2-fold increase in reporter activity. Conditioning with TGF-β did not prolong the half-life of LTC 4 synthase mRNA, as assessed by RNase protection assays in actinomycin D-treated cells. Cycloheximide exposure experiments revealed that new protein synthesis was not required for the observed stimulatory effect of TGF-β on LTC 4 synthase mRNA. We conclude that LTC 4 synthase expression is increased at a transcriptional level by TGF-β in mononuclear phagocytes.