Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester.
Growth factors and tumor promoters have been shown to play a role in intestinal epithelial growth regulation and transformation. In this study, transforming growth factor-alpha (TGF alpha) and the tumor promoter, tetradecanoyl phorbol acetate (TPA), are shown to stimulate the production of eicosanoids by rat intestinal epithelial (RIE-1) cells in culture. A 4.5-kb mRNA, which hybridizes to the mouse cyclooxygenase-2 cDNA probe, is elevated 18-fold within 30 min after TGF alpha or TPA treatment. Stimulation of RIE-1 cells with TGF alpha leads to the increase of a protein (M(r) approximately 69,000), which binds a monospecific antibody to the mouse cyclooxygenase-2 protein. Dexamethasone markedly inhibits the increase of the 4.5-kb mRNA. Pretreatment of TGF alpha or TPA-stimulated RIE-1 cells with dexamethasone or cyclooxygenase inhibitors prevents the increase in eicosanoid production by these cells. Treatment of quiescent RIE-1 cells with TGF alpha stimulates mitogenesis. This mitogenic activity is blocked by pretreating the cells with dexamethasone or cyclooxygenase inhibitors. A mitogen-inducible cyclooxygenase gene is thus shown to be regulated by TGF alpha and TPA in rat intestinal epithelial cells. We suggest that products of an intestinal growth factor-inducible cyclooxygenase may play a role in the regulation of mitogenesis.
DuBois
R N
RN
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Awad
J
J
Morrow
J
J
Roberts
L J
LJ
Bishop
P R
PR
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D015342:DNA Probes; D015777:Eicosanoids / Q000096:biosynthesis*; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D004790:Enzyme Induction; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
D015342:DNA Probes; D015777:Eicosanoids; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D013467:Sulindac; C025462:sulindac sulfide; D004247:DNA; D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine; D007213:Indomethacin