Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-γ

Jianwen Feng, Jihong Han, S. Freida A. Pearce, Roy L. Silverstein, Antonio M. Gotto, David P. Hajjar, Andrew C. Nicholson

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

CD38, 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 flint 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-γ (peroxisome proliferator activated receptor-γ). Other PPAR-γ ligands (15- deoxyΔ12,14 prostaglandin J2 (15d-PGJ2) 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 RAW284.7 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-PGJ2, OxLDL and IL-4. In addition, PKC inhibitors decreased both PPAR-γ mRNA and protein expression and blocked induction of CD36 protein surface expression by OxLDL and 15d-PGJ2 in human monocytes, as determined by FACS. 15d-PGJ2 had no effect on translocation of PKC-α 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-γ activation. Defining these signaling pathways is critical for understanding and modulating expression of this scavenger receptor pathway.

Original languageEnglish (US)
Pages (from-to)688-698
Number of pages11
JournalJournal of lipid research
Volume41
Issue number5
StatePublished - May 2000

Keywords

  • CD36
  • Macrophage
  • PPAR-γ
  • Scavenger receptor PKC

ASJC Scopus subject areas

  • Endocrinology

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