Downregulation 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 of 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 E2 (PGE2) production by U937 cells was enhanced by AFP. Pretreatment with indomethacin, a cyclooxygenase inhibitor, reversed AFP-inhibited TNF-alpha production by 78%. Thus, we conclude that AFP downregulates TNF-alpha and IL-1 beta production via a PGE2-dependent mechanism.
Wang
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W
Department of Medicine (Gastroenterology Division), Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Alpert
E
E
D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D000509:alpha-Fetoproteins / Q000494:pharmacology*
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000509:alpha-Fetoproteins; D007371:Interferon-gamma; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate