Synthesis of Sterols and 5-Lipoxygenase Products are Required for the G<sub>1</sub>-S Phase Transition of Interleukin-2-Dependent Lymphocyte Proliferation

J-STAGE
  • HATA Shingo
    Department of Pathology, Institute for Virus Research, Kyoto University
  • SUGAMA Kazushige
    Department of Serology and Immunology, Institute for Virus Research, Kyoto University
  • YOU-LI Zu
    Department of Pathology, Institute for Virus Research, Kyoto University
  • HATANAKA Masakazu
    Department of Serology and Immunology, Institute for Virus Research, Kyoto University
  • NAMBA Yuziro
    Department of Pathology, Institute for Virus Research, Kyoto University
  • HANAOKA Masao
    Department of Pathology, Institute for Virus Research, Kyoto University

Abstract

A murine killer T cell line, G-CTLL 1, whose proliferation depends on the presence of interleukin 2 (IL-2), was used to analyze the mechanism of IL-2 action with respect to sterol synthesis and arachidonate metabolism. De novo sterol synthesis was substantially enhanced much earlier than DNA synthesis, and the rate reached a maximum at 13hr after the addition of IL-2. Compactin, which is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase, the enzyme in the rate-limiting step of the sterol synthesis), inhibited the IL-2-induced DNA synthesis. The addition of mevalonate, the product of HMG CoA reductase, prevented the inhibition of DNA synthesis by compactin, suggesting that the supply of a sufficient amount of sterol is an essential prerequisite for IL-2 action. The IL-2-induced DNA synthesis was also inhibited by AA861, a specific inhibitor of arachidonate 5-lipoxygenase, and by other lipoxygenase inhibitors such as nordihydroguaiaretic acid and esculetin. In contrast, indomethacin, an inhibitor of arachidonate cyclooxygenase, had no effect. These findings suggest that synthesis of 5-lipoxygenase products is also a prerequisite. The inhibition of DNA synthesis was effectively inhibited only when compactin or lipoxygenase inhibitors were added early enough to block the synthesis of sterols or 5-lipoxygenase products; addition of the reagents after 3hr decreased the inhibition with time. Therefore, about 3hr after the addition of IL-2, several drastic intracellular changes are assumed to begin and to lead to DNA synthesis.

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