on April 6, 2006
Published online before print April 6, 2006, doi: 10.1161/01.ATV.0000220383.19192.55
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Submitted on July 26, 2005
Accepted on March 23, 2006
Transforming Growth Factor-
-Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2
Nishi N. Singh and Dipak P. Ramji *
From the Cardiff School of Biosciences, Cardiff University, United Kingdom.
* To whom correspondence should be addressed. E-mail: Ramji{at}cardiff.ac.uk.
Objective--The cytokine transforming growth factor-
(TGF-) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF- 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- 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- activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF- 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-, 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--induced expression of apoE.
Key words: apolipoprotein E • atherosclerosis • macrophage • TGF-
; signal transduction and gene expression
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