Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers andhalogenated hydrocarbons induce peroxisomes in hepatocytes, and causehepatocellular adenoma and carcinoma in rats and mice. The mechanism bywhich these agents act is unknown, although recent studies have suggested alink between increased cell proliferation and hepatic cancer caused byperoxisome proliferators. Here, we demonstrate that neutralizing antibodiesto tumor necrosis factor alpha (TNF alpha) block increases in proteinkinase C and cell proliferation due to [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), ahypolipidemic drug and potent peroxisome proliferator that causes tumors.WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNFalpha was detected immunohistochemically exclusively in Kupffer cells.These results demonstrate that WY-14,643 acts as an indirect mitogen onhepatocytes via TNF alpha. We propose that the Kupffer cell, a major sourceof TNF alpha in the liver, is involved in the mechanism of the mitogeniceffect of WY-14,643.