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

Journal Article · Sun Jan 01 04:00:00 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), Journal Name: Int. J. Mod. Phys. A; (United States) Vol. 9:1; ISSN IMPAE
• Country of Publication: United States
• Language: English

Related Subjects

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