Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages

Blood. 2009 Jan 1;113(1):165-74. doi: 10.1182/blood-2008-05-158048. Epub 2008 Oct 15.

Abstract

Human protein S is an anticoagulation protein. However, it is unknown whether protein S could regulate the expression and function of macrophage scavenger receptor A (SR-A) in macrophages. Human THP-1 monocytes and peripheral blood monocytes were differentiated into macrophages and then treated with physiological concentrations of human protein S. We found that protein S significantly reduced acetylated low-density lipoprotein (AcLDL) uptake and binding by macrophages and decreased the intracellular cholesteryl ester content. Protein S suppressed the expression of the SR-A at both mRNA and protein levels. Protein S reduced the SR-A promoter activity primarily through inhibition in the binding of transcription factors to the AP-1 promoter element in macrophages. Furthermore, human protein S could bind and induce phosphorylation of Mer receptor tyrosine kinase (Mer RTK). Soluble Mer protein or tyrosine kinase inhibitor herbimycin A effectively blocked the effects of protein S on AcLDL uptake. Immunohistochemical analysis revealed that the level of protein S was substantially increased in human atherosclerotic arteries. Thus, human protein S can inhibit the expression and activity of SR-A through Mer RTK in macrophages, suggesting that human protein S is a modulator for macrophage functions in uptaking of modified lipoproteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Cholesterol Esters / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Oncogene Proteins / metabolism
  • Protein Binding / drug effects
  • Protein Binding / immunology
  • Protein S / metabolism*
  • Protein S / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / metabolism*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • U937 Cells
  • c-Mer Tyrosine Kinase

Substances

  • Cholesterol Esters
  • Lipoproteins, LDL
  • MSR1 protein, human
  • Oncogene Proteins
  • Protein S
  • Proto-Oncogene Proteins
  • Scavenger Receptors, Class A
  • acetyl-LDL
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • TYRO3 protein, human
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase