Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res 2000 May;41(5):688-96
Date
04/29/2000Pubmed ID
10787429Scopus ID
2-s2.0-0034123963 (requires institutional sign-in at Scopus site) 222 CitationsAbstract
CD36, a class B scavenger receptor, is a macrophage receptor for oxidized low density lipoprotein (OxLDL) and may play a critical role in atherosclerotic foam cell formation. We have previously demonstrated that OxLDL, macrophage-colony stimulating factor (M-CSF), and interleukin-4 (IL-4) enhanced expression of CD36. The effect of OxLDL on CD36 is due, in part, to its ability to activate the transcription factor, PPAR-gamma (peroxisome proliferator activated receptor-gamma). Other PPAR-gamma ligands (15-deoxyDelta(12,14) prostaglandin J(2) (15d-PGJ(2)) and the thiazolidinedione class of antidiabetic drugs) also increase CD36 expression. We have now evaluated signaling pathways involved in the induction of CD36. Treatment of RAW264.7 cells (a murine macrophage cell line) with protein kinase C (PKC) activators (diacylglycerol and ingenol) up-regulated CD36 mRNA expression. Specific inhibitors of PKC reduced CD36 expression in a time-dependent manner, while protein kinase A (PKA) and cyclic AMP agonists had no effect on CD36 mRNA expression. PKC inhibitors reduced basal expression of CD36 and blocked induction of CD36 mRNA by 15d-PGJ(2), OxLDL and IL-4. In addition, PKC inhibitors decreased both PPAR-gamma mRNA and protein expression and blocked induction of CD36 protein surface expression by OxLDL and 15d-PGJ(2) in human monocytes, as determined by FACS. 15d-PGJ(2) had no effect on translocation of PKC-alpha from the cytosol to the plasma membrane. These results demonstrate that two divergent physiological or pathophysiological agonists utilize a common pathway to up-regulate of CD36 gene expression. This pathway involves initial activation of PKC with subsequent PPAR-gamma activation. Defining these signaling pathways is critical for understanding and modulating expression of this scavenger receptor pathway.
Author List
Feng J, Han J, Pearce SF, Silverstein RL, Gotto AM Jr, Hajjar DP, Nicholson ACAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBase Sequence
CD36 Antigens
Cell Line
DNA, Complementary
Enzyme Activation
Enzyme Inhibitors
Gene Expression Regulation
Humans
Interleukin-4
Lipoproteins, LDL
Mice
Monocytes
Prostaglandin D2
Protein Kinase C
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Signal Transduction
Transcription Factors