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 (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-alpha) and interleukin-1 beta (IL-1 beta) are important cytokines in immunoregulation, we investigated whether AFP could modulate TNF-alpha and IL-1 beta production in U937, a human monocytic cell line, Our results showed that U937 cells secreted TNF-alpha and IL-1 beta in response to either phorbyl 12-myristate 13-acetate (PMA) or IFN-gamma + LPS. In contrast, AFP significantly suppressed PMA-induced TNF-alpha and IL-1 beta 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-alpha and IL-1 beta production by 58% and 67%, respectively, AFP also inhibited interferon-gamma plus lipopolysaccharide (IFN-gamma + LPS)-induced TNF-alpha and IL-1 beta production, Furthermore, Northern blot analysis showed that AFP suppressed PMA-mediated TNF-alpha and IL-1 beta messenger RNA (mRNA) expression. PMA-induced prostaglandin E(2) (PGE(2)) production by U937 cells was enhanced by AFP, Pretreatment with indomethacin, a cyclooxygenase inhibitor, reversed AFP-inhibited TNF-alpha production by 78%. Thus, me conclude that AFP downregulates TNF-alpha and IL-1 beta production via a PGE(2)-dependent mechanism.