Counteracting Effects Of Dexamethasone And Alpha-2-Macroglobulin On Inhibition Of Proliferation Of Normal And Neoplastic Rat Hepatocytes By Transforming Growth Factors-Beta Type-1 And Type-2

Primary cultures of hepatocytes isolated from normal F-344 rats or from beta-2 of both surrounding and neoplastic hepat Both DEX and alpha-2-M were chemical carcinogenesis were used to determine if dexamethasone (DEX) or alpha-2-macroglobulin (alpha-2-M) modify the ability of transforming growth factors-beta type 1 (TGF-beta-1) and type 2 (TGF-beta-2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF-beta-1 and beta-2 were equivalently potent inhibitors of S-phase DNA synthesis in normal and neoplastic hepatocytes as determined by H-3-thymidine autoradiography. Both DEX (1 to 100-mu-M) and alpha-2-M (50-200-mu-M) partially counteracted the mito-inhibitory effect of both TGF-beta-s on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive alpha-2-M and were less able to overcome the inhibitory effect of TGF-beta than normal or surrounding hepatocytes. Purified bovine alpha-2M partially counteracted the inhibition of TGF-beta-1 or beta-2 of both surrounding and neoplastic hepatocytes. Both DEX and alpha-2-M were more effective against the mito-inhibitory activity of TGF-beta-2. Our data suggest that alpha-2-M released by DEX-treated normal hepatocytes contributes to the counteraction of the TGF-beta effect by DEX. Our results support the hypothesis that glucocorticoids and growth-factor-binding proteins may have important roles in modulating the effects of TGF-beta on normal hepatocyte proliferation and suggest that under some conditions hepatocellular neoplasms can be more sensitive than normal hepatocytes to inhibition of proliferation by TGF-beta.