Effects of theophylline and dibutyryl cyclic AMP on proliferation and keratinization of human keratinocytes

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Abstract
Recent evidence suggested that cyclic[c]AMP may be involved in the regulation of cell proliferation and differentiation. The effects of theophylline and dibutyryl cAMP on cell division and keratinization of human epidermal cultures were examined. Nine to 12-day-old cultures were treated with these agents, separately and in combination, for various intervals. Both agents, either singly or in combination, depressed mitoses. The maximum mitotic inhibition was obtained in cultures treated with theophylline or theophylline plus dibutyryl cAMP. Tritiated thymidine studies showed that the test agents had no effect on labeling index (LI) at 4 h, but a 74% inhibition of LI was observed at 24 h. The maximum inhibition of LI (93%) occurred at 96 h. In contrast to the control cultures, which rarely contain keratohyaline granules (KG), a marked increase in the production of these granules occurred in cultures treated with dibutyryl cAMP plus theophylline. The KG were present over the whole outgrowth. Theophylline alone also stimulated the production of KG, whereas dibutyryl cAMP had no effect. These agents inhibit cell division and this inhibition may be accompanied by an increased production of KG.