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TGF-ß Increases Leukotriene C₄ Synthase Expression in the Monocyte-Like Cell Line, THP-1¹

^* Department of Veterans Affairs Medical Center, San Diego, CA 92161, and Department of Medicine, University of California at San Diego, La Jolla, CA 92037

The goal of this study was to determine whether cytokines modulate leukotriene C₄ (LTC₄) synthase expression in mononuclear phagocytes. A panel of cytokines was surveyed for changes in LTC₄ synthase mRNA in THP-1 cells. TGF-ß1, -2, and -3 had significant stimulatory effects. The addition of TGF-ß resulted in a time-dependent increase in LTC₄ synthase mRNA at 6 h, which persisted through 48 h. Furthermore, this conditioning resulted in an increase in immunoreactive protein for LTC₄ synthase through 7 days. TGF-ß conditioning of cells resulted in a time- and dose-dependent increase in stimulated LTC₄ synthase activity. Following transient transfection of THP-1 cells with a promoter-reporter construct containing 1.2 kb of the LTC₄ synthase promoter, TGF-ß treatment resulted in a 2-fold increase in reporter activity. Conditioning with TGF-ß did not prolong the half-life of LTC₄ 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-ß on LTC₄ synthase mRNA. We conclude that LTC₄ synthase expression is increased at a transcriptional level by TGF-ß in mononuclear phagocytes.

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