title: Paraoxonase 1 (PON1) inhibits monocyte-to-macrophage differentiation.
abstract: OBJECTIVE
  To analyze paraoxonase 1 (PON1) effect on monocyte-to-macrophage differentiation.
  
  
  RESULTS
  THP-1 monocytic cell-line and mouse peritoneal macrophages (MPM) were studied. Markers for monocytes differentiation included: morphological changes, CD11b and CD36 expression, and cellular oxidative stress. PON1KO MPM were more differentiated than control C57BL/6 MPM. Intraperitoneal injection of recombinant PON1 (rePON1) to C57BL/6 or to PON1KO mice significantly increased serum, MPM, and tissues PON1 activities. These effects were associated with a significant decrease in CD11b in C57BL/6 and PON1KO MPM (by 21% and 35%, respectively), in CD36 (by 35% and 38%, respectively), and in cellular total peroxides content (by 18% and 20%, respectively). rePON1 also significantly inhibited CD11b and CD36 expression, and cellular total peroxides during PMA-induced THP-1 monocytes differentiation, by 68%, 56% and 53%, respectively. Similar effects were observed upon using reconstituted HDL (rHDL) +rePON1, or human HDL +rePON1, in comparison to rHDL or to human HDL, as well as, HDL from C57BL/6 vs. PON1KO mice. Inhibition of monocyte-to-macrophage differentiation was demonstrated also by several dietary antioxidants such as vitamin E, gallic acid, or punicalagin (the major polyphenol in pomegranate). Whereas NADPH oxidase was not involved in PON1 anti-differentiation effect, mitochondrial complex I could be involved, as rotenone (complex I inhibitor) significantly decreased (by 77%) the expression of CD11b during THP-1 differentiation. Finally, blocking PON1 sulfhydryl group with N-ethylmalemide significantly attenuated PON1 inhibitory effect on THP-I monocyte-to-macrophage differentiation.
  
  
  CONCLUSIONS
  HDL-associated PON1 inhibits monocyte-to-macrophage differentiation, and this effect could be related to PON1 peroxidase-like activity which involves its free sulfhydryl group.
authors.affiliation: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
authors.forename: Mira
authors.initials: M
authors.lastname: Rosenblat
authors.forename: Nina
authors.initials: N
authors.lastname: Volkova
authors.forename: John
authors.initials: J
authors.lastname: Ward
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D043303:Aryldialkylphosphatase / Q000172:deficiency / Q000378:metabolism*; D039481:CD11b Antigen / Q000096:biosynthesis; D018955:CD36 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects*; D005707:Gallic Acid / Q000494:pharmacology; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D039481:CD11b Antigen; D018955:CD36 Antigens; D047348:Hydrolyzable Tannins; D010545:Peroxides; D014810:Vitamin E; D005707:Gallic Acid; C115642:punicalagin; D019255:NADPH Oxidases; D043303:Aryldialkylphosphatase