Downregulation of phorbol 12-myristate 13-acetate–induced tumor necrosis factor–alpha and interleukin-1β production and gene expression in human monocytic cells by human alpha-fetoprotein

Authors

  • Wei Wang,

    1. Department of Medicine (Gastroenterology Division), and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis–Jewish General Hospital, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Elliot Alpert MD

    Corresponding author
    1. Department of Medicine (Gastroenterology Division), and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis–Jewish General Hospital, and the Department of Medicine, McGill University, Montreal, Quebec, Canada
    • Department of Medicine SMBD–Jewish General Hospital, and McGill University, 3755 Cote St, Catherine Rd, Montreal, Quebec H3T 1E2, Canada
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Abstract

We previously identified a specific receptor for alpha-fetoprotein (AFP) on human monocytes. Although AFP alters many immune cell functions, the effect of AFP on monocyte cytokine production is unknown. Because tumor necrosis factor–alpha (TNF-α) and interleukin-1β (IL-1β) are important cytokines in immunoregulation, we investigated whether AFP could modulate TNF-α and IL-1β production in U937, a human monocytic cell line. Our results showed that U937 cells secreted TNF-α and IL-1β in response to either phorbyl 12-myristate 13-acetate (PMA) or IFN-γ + LPS. In contrast, AFP significantly suppressed PMA-induced TNF-α and IL-1β production by U937 cells in a time and dose dependent fashion. Pretreatment of U937 cells with AFP resulted in maximal inhibition of PMA-stimulated TNF-α and IL-1β production by 58% and 67%, respectively. AFP also inhibited interferon-γ plus lipopolysaccharide (IFN-γ + LPS)–induced TNF-α and IL-1β production. Furthermore, Northern blot analysis showed that AFP suppressed PMA-mediated TNF-α and IL-1β messenger RNA (mRNA) expression. PMA-induced prostaglandin E2 (PGE2) production by U937 cells was enhanced by AFP. Pretreatment with indomethacin, a cyclooxygenase inhibitor, reversed AFP-inhibited TNF-α production by 78%. Thus, we conclude that AFP downregulates TNF-α and IL-1β production via a PGE2-dependent mechanism. (Hepatology 1995; 22:921–928.)

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