Suppression of interleukin-1 beta and LDL scavenger receptor expression in macrophages by a selective protein kinase C inhibitor.
A human monocytic cell line, THP-1, stimulated with 40 nM phorbol myristate acetate (PMA), differentiated to macrophage-like cells, and exhibited increased expression and release of interleukin-1 beta and expression of acetylated low density lipoprotein (ac-LDL) receptors. A selective inhibitor, MDL 29,152 (4-propyl-5-(4-quinolinyl)-2(3H)-oxazolone) was used to show that this induction required activation of protein kinase C. MDL 29,152 acts in the catalytic domain of protein kinase C and is at least 200-fold selective for protein kinase C over cAMP-dependent protein kinase in THP-1 cells. MDL 29,152 (50 microM) reduced levels of interleukin-1 beta mRNA in PMA-stimulated cells by 76% and eliminated detectable interleukin-1 beta in the media. Flow cytometric analysis showed that 48 h after THP-1 activation, approximately 50% of the cells expressed ac-LDL receptors, while in the presence of 100 microM MDL 29,152, less than 5% of the cells expressed receptors. The relationship between THP-1 differentiation and protein kinase C activation was determined by following the expression of the cell surface antigen MO-1. Expression of MO-1 antigen increases as monocytes differentiate to macrophages. After 48 h of phorbol activation, 90% of the THP-1 population was MO-1-positive; less than 16% of the population was MO-1-positive when 100 microM MDL 29,152 was present. By dual analysis, it was found that within the differentiated, MO-1-positive population, only approximately 50% of the cells also expressed ac-LDL receptors. Based on these findings, we conclude that protein kinase C promotes processes important in THP-1 activation and differentiation to macrophage-like cells including interleukin-1 beta expression and secretion, ac-LDL receptor and MO-1 expression.
Akeson
A L
AL
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Schroeder
K
K
Woods
C
C
Schmidt
C J
CJ
Jones
W D
WD
D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D010081:Oxazolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D011973:Receptors, LDL / Q000096:biosynthesis*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007375:Interleukin-1; D008565:Membrane Proteins; D011804:Quinolines; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C073398:MDL 29152; D010081:Oxazolone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate