title: SIRT1 inhibits differentiation of monocytes to macrophages: amelioration of synovial inflammation in rheumatoid arthritis.
abstract: Monocyte-to-macrophage differentiation plays a central role in the pathophysiology of rheumatoid arthritis (RA)-associated inflammation because it results in the secretions of various inflammatory mediators in inflamed synovium, and thus, this differentiation is viewed as a clinical target. We aimed to determine whether SIRT1 inhibits the differentiation of monocytes from RA patients into macrophages by suppressing PU.1 phosphorylation. Monocytes from synovial fluid of RA patients (RAMCs), THP-1 monocytes, and mouse bone marrow-derived monocytes (BMDCs) were studied. The phorbol 12-myristate 13-acetate (PMA)-stimulated RA monocyte adherence was significantly inhibited by resveratrol (a SIRT1 activator), and this inhibition by resveratrol was prevented by pretreating cells with sirtinol (a SIRT1 inhibitor). Furthermore, resveratrol pretreatment inhibited PMA-induced expressions of macrophage surface markers (CD11b, CD14, and CD36) and PMA-induced NF-κB transcriptional activation and, thus, suppressed the secretions of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). In SIRT1 transgenic (Tg) mice, monocyte differentiation was inhibited and NF-κB transcriptional activity was suppressed and the expressions of TNF-α, IL-1β, and IL-6 were decreased at the protein and mRNA levels versus control C57BL/6 mice. Furthermore, SIRT1 activation by resveratrol suppressed PMA-induced phosphorylation and the nuclear translocation of PU.1 and, thus, inhibited monocyte differentiation. In conclusion, SIRT1 appears to inhibit monocyte to macrophage differentiation by suppressing PU.1 phosphorylation and inflammatory signaling, which suggests SIRT1 plays a critical role in the regulation of synovial inflammation in RA.
  
  
  
  SIRT1 overexpression inhibits monocyte to macrophage differentiation. SIRT1 suppresses PU.1 phosphorylation. Inactivation of PU.1 phosphorylation inhibits monocyte differentiation. SIRT1 regulates inflammation by inhibiting NF-κB during monocyte differentiation.
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, College of Medicine, Dong-A University, Busan, 49202, Republic of Korea.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, Dong-A University, Busan, 49202, Republic of Korea.
authors.forename: Sang Yeob
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea.
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea.
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea. chidkim@pusan.ac.kr.|Department of Pharmacology, School of Medicine, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea. chidkim@pusan.ac.kr.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D056564:Sirtuin 1; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C447939:SIRT1 protein, human
keywords: Inflammation; Monocyte-to-macrophage differentiation; Rheumatoid arthritis; SIRT1