Transforming growth factor-β-induced expression of the apolipoprotein E gene requires c-Jun N-terminal kinase, p38 kinase, and casein kinase 2

Abstract

OBJECTIVE - The cytokine transforming growth factor-β (TGF-β) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-β have not been characterized and were therefore investigated. METHODS AND RESULTS - Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-β induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-β activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-β also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-β, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1. CONCLUSIONS - These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-β-induced expression of apoE. © 2006 American Heart Association, Inc.