Relationship between TGF alpha-induced DNA synthesis and prostaglandin synthesis in human HaCaT keratinocytes.
The relationship between transforming growth factor alpha (TGF alpha)-induced cell proliferation and prostaglandin synthesis was investigated using growth-arrested human keratinocytes of the HaCaT line. Depending on the TGF alpha concentration, the stimulation of DNA synthesis (5-fold) was found to be either insensitive (at < 10 ng/ml TGF alpha) or sensitive (at > or = 20 ng/ml TGF alpha) to inhibition by both indomethacin, an inhibitor of prostaglandin synthases (PGHS) 1 and 2 and the PGHS 2-specific inhibitor NS-398. Indomethacin-effected inhibition did not correlate with cytotoxicity and was restricted to a narrow time window after growth factor administration. The indomethacin- and NS-398-sensitive mitogenic effect of TGF alpha correlated with an early increase of arachidonic acid release and prostaglandin (PGE2, PGF2alpha) synthesis, whereas the PGHS inhibitor-insensitive TGF alpha effect did not. TGF alpha-induced prostaglandin synthesis was due to a growth factor-induced PGHS-2 activity as indicated by its suppression by NS-398. However, attempts to overcome the PGHS inhibitor-dependent suppression of TGF alpha-induced DNA synthesis by adding prostaglandins (E1, E2, F2alpha, G2) to the cultures proved to be unsuccessful. Thus, TGF alpha-induced synthesis of prostaglandins seems not to be involved in the mediation of the mitogenic effect of the growth factor on human keratinocytes in culture.
Hanke
B
B
Research Program Tumor Cell Regulation, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg.
Fürstenberger
G
G
Marks
F
F
D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; D016211:Transforming Growth Factor alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016718:Arachidonic Acid; D004247:DNA; D007213:Indomethacin