Dexamethasone selectively inhibits WY14,643-induced cell proliferation andnot peroxisome proliferation in mice

It has been proposed that the hepatocellular proliferation induced by perox isome proliferators may occur through an indirect mechanism involving cytok ine release as opposed to direct regulation of cell growth genes by PPAR al pha. We compared the induction of peroxisome proliferation and cell prolife ration in C57Bl/6 mice treated with 100 mg/kg/day WY14,643 in the presence or absence of increasing doses of dexamethasone (DEX), an inhibitor of the release of proinflammatory cytokines, Biochemical markers of peroxisome pro liferation, including fatty acyl-CoA oxidase activity, CYP4A content, and l iver-to-body-weight ratios were markedly increased in the WY14,643-treated mice. DEX coadministration, up to a maximum dose of 50 mg/kg/day, did not p revent the induction of these parameters. Acyl-CoA oxidase mRNA levels incr eased 5-fold with WY14,643 treatment and 15-fold with DEX coadministration at 5 mg/kg/day. ApoCIII mRNA levels were decreased by 50% in WY14,643-treat ed mice. DEX alone at 5 mg/kg/day increased the ApoCIII mRNA 4-fold, but WY 14,643 coadministration also inhibited this induction by greater than 50%, In addition, immunohistochemical detection of peroxisomes with anti-PMP-70 antibody demonstrated marked increase in hepatocellular peroxisomes in WY14 ,643-treated mice regardless of DEX treatment, In contrast, coadministratio n of DEX at 2 mg/kg/day partially inhibited the hepatocyte proliferation re sponse (measured by BrdU incorporation or Ki-67 immunohistochemical detecti on). Moreover, DEX at doses of 5 mg/kg/day or higher completely inhibited t he induction of cell proliferation and, at these higher doses, reduced the cell proliferation rate to levels below the vehicle-treated control mice. O ur studies clearly demonstrate that the hepatocellular proliferation induce d by a peroxisome proliferator can be modulated independently of the other pleiotropic effects usually induced by these agents, suggesting an indirect mechanism of hyperplasia. (C) 2001 Academic Press.