Regulatory Effects of Multifunctional Cytokines and Steroid Hormones on Apolipoprotein B Production by Human Fetal Hepatocytes

OBJECTIVE: The purpose of the present investigation was to determine the effects of certain multifunctional cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and IL-6) and steroid hormones (estradiol, testosterone, progesterone, and cortisol) on the production of apolipoprotein B (Apo B) by cultured human fetal hepatocytes. We conducted these experiments because of our recent observations that purified human fetal Kupffer cells produce TNF-α, IL-1β, and IL-6. METHODS: Human fetal hepatocytes, specifically depleted of hematopoietic precursors and Kupffer cells, were cultured in defined medium. The amounts of Apo B released into the culture medium were measured by a sensitive and specific enzyme-linked immunosorbent assay. RESULTS: Hepatocytes (106 cells) produced 82 ± 16 ng Apo B per 24 hours during days 4-7 in culture. Results demonstrated that treatment of cultured hepatocytes with TNF-α maximally inhibited Apo B production by 50% at a half-maximal concentration of 100 pg/mL, whereas IL-1β maximally inhibited Apo B production by 80% at a half-maximal dose of 200 pg/mL. Cells exposed to IL-6 produced increased amounts of Apo B, but only after IL-6 was removed from the culture medium. The addition of TNF-α, IL-1β, or IL-6 did not significantly affect hepa tocyte viability. At physiologic concentrations (1 μmol/L), estrogens were able to increase the production of Apo B by 25-65%; however, no positive or negative effect could be demonstrated with dexamethasone, cortisol, testosterone, or progesterone. When using synthetic estrogens such as ethinyl estradiol and mestranol, the stimulatory effect was most pronounced. CONCLUSION: Tumor necrosis factor-α and IL-1β have an inhibitory effect and estrogens have a stimulatory effect on Apo B production by human fetal hepatocytes in culture. These studies suggest that fetal hepatocytes can produce Apo B and that the synthesis of Apo B is under the control of multifunctional cytokines and steroid hormones. (J Soc Gynecol Invest 1994 ;1 :256-63).