Regular paper
Relationship between TGFα-induced DNA synthesis and prostaglandin synthesis in human HaCaT keratinocytes

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Abstract

The relationship between transforming growth factor α (TGFα)-induced cell proliferation and prostaglandin synthesis was investigated using growth-arrested human keratinocytes of the HaCaT line. Depending on the TGFα concentration, the stimulation of DNA synthesis (5-fold) was found to be either insensitive (at ≤ 10 ng/ml TGFα) or sensitive (at ≥ 20 ng/ml TGFα) 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 TGFα correlated with an early increase of arachidonic acid release and prostaglandin (PGE2, PGF) synthesis, whereas the PGHS inhibitor-insensitive TGFα effect did not. TGFα-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 TGFα-induced DNA synthesis by adding prostaglandins (E1, E2, F, G2) to the cultures proved to be unsuccessful. Thus, TGFα-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.

Keywords

Transforming growth factor α
Prostaglandin
Keratinocyte
Mitogenic signaling

Abbreviations

TGFα
transforming growth factor α
EGF
epidermal growth factor
PGE2
prostaglandin E2
PGF
prostaglandin F
PGG2
prostaglandin G2
PBS
phosphate-buffered saline
MTT
3-[4,5-dimethylthiazol-2-yl]-2,5,diphenyltetrazolium bromide
[3H]dR
[methyl-3H]thymidiline

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