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BACKGROUND & AIMS: Tumor necrosis factor (TNF) alpha mediates both liver injury and regeneration. Kupffer cells are thought to produce TNF because gadolinium chloride (GdCl), a drug that depletes Kupffer cells, prevents TNF-mediated injury. However, GdCl increases liver TNF and regeneration after partial hepatectomy (PH), suggesting that other cells produce TNF during regeneration. The aim of this study was to identify the source(s) of TNF after PH in normal and Kupffer cell- depleted rats. METHODS: Livers were harvested at 0, 1, or 48 hours after PH from saline- or GdCl-treated rats. TNF expression was evaluated by in situ reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: In saline-treated rats, neither TNF transcripts nor protein was detected before PH, but both increased after PH. One hour after PH, 64% +/- 8% portal areas had TNF-positive bile ducts or veins and 61% +/- 1% central veins were TNF positive; by 48 hours, 57% +/- 1% portal areas, 40% +/- 1% central veins, and a few sinsusoidal cells expressed TNF. In GdCl-treated rats, TNF was expressed in 22% +/- 6% portal areas before PH; in 76% +/- 3% portal areas and 75% central veins at 1 hour; and in 88% +/- 2% portal areas and 80% +/- 9% central veins at 48 hours after PH. CONCLUSIONS: In the regenerating livers of both normal and Kupffer cell-depleted rats, bile ducts and veins are the predominant sources of TNF-alpha. (Gastroenterology 1997 Jun;112(6):2089-98)