DOWN-REGULATION OF PHORBOL 12-MYRISTATE 13-ACETATE-INDUCED TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA PRODUCTION AND GENE-EXPRESSION IN HUMAN MONOCYTIC CELLS BY HUMAN ALPHA-FETOPROTEIN

We previously identified a specific receptor for alpha-fetoprotein (AF P) on human monocytes, Although AFP alters many immune cell. functions , the effect of AFP on monocyte cytokine production is unknown, Becaus e tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are important cytokines in immunoregulation, we investigated wh ether AFP could modulate TNF-alpha and IL-1 beta production in U937, a human monocytic cell line, Our results showed that U937 cells secrete d TNF-alpha and IL-1 beta in response to either phorbyl 12-myristate 1 3-acetate (PMA) or IFN-gamma + LPS. In contrast, AFP significantly sup pressed PMA-induced TNF-alpha and IL-1 beta production by U937 cells i n a time and dose dependent fashion. Pretreatment of U937 cells with A FP resulted in maximal inhibition of PMA-stimulated TNF-alpha and IL-1 beta production by 58% and 67%, respectively, AFP also inhibited inte rferon-gamma plus lipopolysaccharide (IFN-gamma + LPS)-induced TNF-alp ha and IL-1 beta production, Furthermore, Northern blot analysis showe d that AFP suppressed PMA-mediated TNF-alpha and IL-1 beta messenger R NA (mRNA) expression. PMA-induced prostaglandin E(2) (PGE(2)) producti on by U937 cells was enhanced by AFP, Pretreatment with indomethacin, a cyclooxygenase inhibitor, reversed AFP-inhibited TNF-alpha productio n by 78%. Thus, me conclude that AFP downregulates TNF-alpha and IL-1 beta production via a PGE(2)-dependent mechanism.