Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester

Journal Article · Sun Jan 01 00:00:00 EST 1989 · Int. J. Mod. Phys. A; (United States)

DOI:https://doi.org/10.1128/MCB.9.1.252· OSTI ID:5703275

Horiguchi, J; Spriggs, D; Imamura, K; Stone, R; Luebbers, R; Kufe, D

The treatment of human HL-60 promyelocytic leukemia cells with 12-0 tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcripts. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNS mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase, A/sub 2/ blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B/sub 4/. In contrast, the cyclooxygenase metabolite prostaglandin E/sub 2/ inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B/sub 4/ and prostaglandin E/sub 2/.

• Research Organization: Harvard Medical School, Boston, MA (USA). Dept. of Pharmacology
• OSTI ID: 5703275
• Journal Information: Int. J. Mod. Phys. A; (United States), Vol. 9:1
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ARACHIDONIC ACID
METABOLITES
LEUKEMIA
TUMOR CELLS
PHORBOL ESTERS
BIOLOGICAL PATHWAYS
TRANSCRIPTION
NECROSIS
BIOSYNTHESIS
ENZYME INHIBITORS
GENE AMPLIFICATION
GENE REGULATION
GENES
MESSENGER-RNA
OXYGENASES
PHENOTYPE
PHOSPHOTRANSFERASES
PROSTAGLANDINS
ANIMAL CELLS
CARBOXYLIC ACIDS
CARCINOGENS
DISEASES
ENZYMES
ESTERS
HEMIC DISEASES
IMMUNE SYSTEM DISEASES
MONOCARBOXYLIC ACIDS
NEOPLASMS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PHOSPHORUS-GROUP TRANSFERASES
RNA
SYNTHESIS
TRANSFERASES
550200* - Biochemistry
550400 - Genetics