title: Tumor necrosis factor production by rat Kupffer cells-regulation by lipopolysaccharide, macrophage activating factor and prostaglandin E2.
abstract: Tumor necrosis factor (TNF) is considered to be deeply involved in the hepatocyte damages in severe hepatitis. To delineate which mediators are involved in the production of TNF in vivo, we examined regulatory mechanisms of the production of TNF by rat Kupffer cells using a variety of mediators. Lipopolysaccharide (LPS) markedly induced TNF production by Kupffer cells. Kinetic studies revealed a rapid release of TNF within 3-4 hrs after the addition of LPS to the culture medium. Spleen cell derived-macrophage activating factor prepared from rat spleen cells did not by itself induce the production of TNF. However, the presence of a small amount of the factor during or before exposure to LPS induced higher levels of TNF, suggesting that macrophage activating factor had a priming effect. Recombinant human interferon-gamma and recombinant human granulocyte-macrophage colony stimulating factor, the natural types of which are components of the macrophage activating factor, displayed similar effects. Prostaglandin E2 (PGE2) and dexamethasone both inhibited LPS-induced TNF production in a dose dependent manner. Indomethacin, a cyclooxygenase inhibitor, increased LPS-induced TNF production. Interestingly, a combination of PGE2 and indomethacin inhibited TNF production more strongly than PGE2 alone, suggesting that the simultaneous treatment with PGE2 and indomethacin decreases liver damage in severe hepatitis rather than PGE2 alone. In addition, PGE2 pretreatment reduced the response to the newly added PGE2, suggesting the presence of a desensitization mechanism in the PGE2 receptor system. These findings suggest that spleen cell-derived macrophage activating factor and bowel-derived LPS take important parts in TNF production through the portal blood in the liver in vivo.
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Ishibashi
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: K
authors.initials: K
authors.lastname: Miki
authors.forename: J
authors.initials: J
authors.lastname: Kudo
authors.forename: Y
authors.initials: Y
authors.lastname: Niho
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016215:Macrophage-Activating Factors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D008070:Lipopolysaccharides; D016215:Macrophage-Activating Factors; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone; D007213:Indomethacin