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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1323.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Transforming Growth Factor-ß–Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2

Nishi N. Singh; Dipak P. Ramji

From the Cardiff School of Biosciences, Cardiff University, United Kingdom.

Correspondence to Dipak P. Ramji, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. E-mail Ramji{at}cardiff.ac.uk

Objective— The cytokine transforming growth factor-ß (TGF-ß) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-ß 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-ß 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-ß activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-ß 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-ß, 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-ß–induced expression of apoE.

The mechanisms underlying the regulation of apolipoprotein E expression in monocytes/macrophages by the antiatherogenic cytokine TGF-ß were investigated. We show a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the response, which have implications to the development of atherosclerosis.

Key Words: apolipoprotein E • atherosclerosis • macrophage • TGF-ß • signal transduction • gene expression

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