TGF-beta 1 inhibits both endotoxin-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene in murine macrophages.
Activated macrophages produce substantial quantities of paracrine mediators, including cytokines, nitric oxide, and prostaglandins. Transforming growth factor beta 1 (TGF-beta) is a potent modulator of immune function. TGF-beta inhibits the cytotoxic activity of endotoxin/lipopolysaccharide (LPS)-activated macrophage cell lines and primary macrophage cultures, reducing their expression of cytokines and nitric oxide. In this report we demonstrate that TGF-beta also attenuates the LPS-induced synthesis and secretion of prostaglandin E2 in murine RAW 264.7 macrophage cells. Macrophage activation also induces accumulation of the recently described ligand-responsive prostaglandin synthase (PGS) TIS10/PGS-2. While TGF-beta alone has no effect on expression from the TIS10/PGS-2 gene, this cytokine inhibits LPS-induced TIS10/PGS-2 protein accumulation and synthesis, as well as LPS-induced TIS10/PGS-2 message accumulation in RAW 264.7 cells. TGF-beta concentrations in the range of 0.1-1.0 ng/ml (4-40 pM) maximally inhibit LPS-induced TIS10/PGS-2 message accumulation. In contrast, neither LPS nor TGF-beta has any effect on the level of PGS-1 (EC 1.14.99.1) message. TGF-beta also attenuates LPS-induced accumulation of unspliced TIS10/PGS-2 transcripts in RAW 264.7 cells, suggesting that this cytokine exerts its effects on TIS10/PGS-2 expression at the transcriptional level. TGF-beta inhibits the LPS-induced accumulation of TIS10/PGS-2 protein and message in cultured murine peritoneal macrophages, as well as in macrophage cell lines.
Reddy
S T
ST
Laboratory of Biomedical and Environmental Sciences, UCLA School of Medicine.
Gilbert
R S
RS
Xie
W
W
Luner
S
S
Herschman
H R
HR
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005091:Exons; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011453:Prostaglandins / Q000096:biosynthesis*; D012326:RNA Splicing; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017931:DNA Primers; D004731:Endotoxins; D008070:Lipopolysaccharides; D011453:Prostaglandins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D011451:Prostaglandin-Endoperoxide Synthases