Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators

WY-14,643 [4-chloro-6-(2,3-xylidino)pyrimidinylthio-acetic acid] is a well-known non-genotoxic carcinogen and peroxisome proliferator that causes liver cancer in rodents by unknown mechanisms. Its ability to sustain elevated rates of hepatocyte DNA synthesis is most likely pivotal in the ultimate development of tumors. The source of this mitogenic stimulus following treatment of rats with WY-14,643 has been hypothesized to be Kupffer cells, the resident hepatic macrophages, since they are activated by peroxisome proliferators in vivo. Therefore, these studies were designed to determine if Kupffer cells are causally responsible for WY-14 643-induced increases in hepatocyte DNA synthesis in vivo. WY-14,643 (100 mg/kg) increased DNA synthesis 8-fold 24 h after treatment; however, inactivation of Kupffer cells with methyl palmitate, a nonhydrolyzable fatty acid ester and known Kupffer cell inhibitor, completely prevented the mitogenic effect of WY-14,643. On the other hand, the ability of WY-14,643 to induce peroxisomes was not affected by methyl palmitate. These data demonstrate that induction of peroxisomes is not dependent on factors from Kupffer cells and support the idea that stimulation of DNA synthesis and induction of peroxisomes occur via distinct mechanisms. Additionally, WY-14,643 increased liver mRNA transcripts of the hepatocyte mitogen tumor necrosis factor alpha (TNF alpha) more than twofold. This increase was also prevented by inactivating Kupffer cells with methyl palmitate. Therefore, it is concluded that Kupffer cells are causally responsible for WY-14,643-induced increases in hepatocyte DNA synthesis most likely by increasing production of TNF alpha, a hepatic mitogen.