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 and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice, The mechanism b y which these agents act is unknown, although recent studies have sugg ested a link between increased cell proliferation and hepatic cancer c aused by peroxisome proliferators, Here, we demonstrate that neutraliz ing antibodies to tumor necrosis factor alpha (TNF alpha) block increa ses in protein kinase C and cell proliferation due to 4-chloro-6-(2,3- xylidido)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic d rug and potent peroxisome proliferator that causes tumors, WY-14,643 m oderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells, Thes e results demonstrate that WY-14,643 acts as an indirect mitogen on he patocytes via TNF Alpha. We propose that the Kupffer cell, a major sou rce of TNF alpha in the liver, is involved in the mechanism of the mit ogenic effect of WY-14,643.