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 (rϾ0.9). 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-␤1 (TGF-␤1) and tumor necrosis factor-␣ (TNF-␣) were very active in inhibiting Lp(a) accumulation in the culture media, with IC 50 s of Ϸ0.3 and 1 ng/mL, respectively. Both TGF-␤1 and TNF-␣ also decreased the apo(a) transcript. Mixing experiments, in which hepatocytes were treated with 10 ng/mL of IL-6 and 0.3 to 10 ng/mL of TGF-␤1 or TNF-␣, demonstrated that the IL-6 -mediated induction of Lp(a) and apo(a) mRNA was ablated with very low levels of either inhibitory cytokine, suggesting a dominant negative effect of TGF-␤1 and TNF-␣. These results show that Lp(a) and apo(a) mRNA expression in primary monkey hepatocytes is subject to both positive (IL-6) and negative (TGF-␤1 and TNF-␣) regulation by physiological levels of cytokines. Thus, in vivo Lp(a) levels may be dependent on the balance between stimulatory and inhibitory cytokines. 1 The Lp(a) particle is formed through the extracellular association of apoB-100 -containing lipoproteins (eg, LDL) to apo(a) through a single disulfide bond.2-7 Apo(a) is highly variable in size and is thought to have arisen by multiple duplications of the plasminogen gene. 8 The concentration of plasma Lp(a) is governed by its production rate and not its catabolism.9 Because apo(a) levels are limiting relative to those of apoB-100, Lp(a) generation is dependent on the amount of apo(a) available for coupling to apoB-100. Apo(a) is synthesized predominately by the liver 10 -12 ; therefore, characterization of factors that modulate hepatic apo(a) expression would lead to a better understanding of Lp(a) regulation.Plasma Lp(a) levels increase after surgery and myocardial infarction. 13 This change in Lp(a) is associated with elevations in several established acute-phase proteins, leading to the suggestion that Lp(a) is an acute-phase reactant and consequently responsive to cytokines such as 14 The latter observation is consistent with the presence of 6 IL-6 cis-acting REs in a 1.4-kb fragment of the human apo(a) gene 5Ј-flanking/promoter region. 15,16 Of these 6 IL-6 REs, 5 are identical in the analogous region of the monkey apo(a) gene. 1...

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