© 1998 American Heart Association, Inc.
Original Contributions |
Dominant Negative Effect of TGF-ß1 and TNF-
on Basal and IL-6–Induced Lipoprotein(a) and Apolipoprotein(a) mRNA Expression in Primary Monkey Hepatocyte Cultures
From the Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Warner-Lambert Co, Ann Arbor, Mich (R.R., M.A.S.); and the Department of Biology, Stetson University, DeLand, Fla (D.B.).
Correspondence to Randy Ramharack, Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Warner-Lambert Co, 2800 Plymouth Rd, Ann Arbor, MI 48105.
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-ß1 (TGF-ß1) and tumor necrosis
factor- (TNF-) were very active in inhibiting Lp(a) accumulation
in the culture media, with IC50s of 
0.3 and 1 ng/mL,
respectively. Both TGF-ß1 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-ß1 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-ß1 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-ß1 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.
Key Words: Lp(a) • apo(a) mRNA • cytokines • monkey hepatocytes
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