Dominant Negative Effect of TGF-β1 and TNF-α on Basal and IL-6–Induced Lipoprotein(a) and Apolipoprotein(a) mRNA Expression in Primary Monkey Hepatocyte Cultures

Abstract—Lipoprotein(a) [Lp(a)] consists of apolipoprotein(a) [apo(a)] disulfide linked to apolipoprotein B-100 of LDL. Elevated plasma Lp(a) is an independent risk factor for a variety of vascular diseases. Lp(a) has been reported to be an acute-phase reactant, suggesting that cytokines may regulate its levels. To determine whether Lp(a) expression was subject to modulation by cytokines, primary monkey hepatocytes that endogenously express Lp(a) were used. Hepatocytes were treated with interleukin (IL)-6, the major mediator of the acute-phase response, and several other cytokines. IL-6 treatment (0.3 to 10 ng/mL) resulted in a marked, dose-dependent, 2- to 4-fold enhancement of Lp(a) accumulation in the hepatocyte culture media that was highly correlated with changes in apo(a) mRNA levels (r>0.9). Several other cytokines, such as IL-2, IL-8, and hepatocyte growth factor, had no significant effect on Lp(a) levels; however, transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were ver...