Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma.
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.
Feng
J
J
Departments of Pathology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Han
J
J
Pearce
S F
SF
Silverstein
R L
RL
Gotto
A M
AM
Hajjar
D P
DP
Nicholson
A C
AC
D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000235:genetics*; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018955:CD36 Antigens; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D015847:Interleukin-4; D011493:Protein Kinase C; D015230:Prostaglandin D2