Protein Kinase C Is Involved in the Induction of ATP-Binding Cassette Transporter A1 Expression by Liver X Receptor/Retinoid X Receptor Agonist in Human Macrophages.
The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have, therefore, investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies, therefore, reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages.
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Etimad A
EA
Huwait
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Nishi N
NN
Singh
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Daryn R
DR
Michael
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Thomas S
TS
Davies
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Joe W E
JW
Moss
Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
Dipak P
DP
Ramji
D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077556:Alitretinoin; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D000071518:Liver X Receptors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D008301:Maleimides / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D006888:Hydroxycholesterols; D007211:Indoles; D000071518:Liver X Receptors; D008301:Maleimides; D057093:Orphan Nuclear Receptors; D047488:Retinoid X Receptors; C003585:22-hydroxycholesterol; D000077556:Alitretinoin; D014212:Tretinoin; D011493:Protein Kinase C; C070515:bisindolylmaleimide I
ATHEROSCLEROSIS; CELL SIGNALING; GENE EXPRESSION; LIVER X RECEPTORS; MACROPHAGES; NUCLEAR RECEPTORS