Year-end Sale % OFF 
Abstract
Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways.
Highlights
Oligodendrocytes (OLGs) are the myelin-forming cells of the central nervous system (CNS)
To determine the role of c-jun in cell cycle activation induced by C5b-9, OLGs were incubated with 20 μM sense (5 -GGTCGTTTCCATCTTTGC3 ) or antisense (5 -GCAAAGAT GGAAACGACC-3 ) c-jun oligonucleotides at 37◦C for 4 h before exposure to activated complement
To determine the role of sirtuin 1 (SIRT1) in cell cycle activation OLGs were preincubated with Sirtinol (200 μM) before exposure to sublytic C5b-9
Summary
Oligodendrocytes (OLGs) are the myelin-forming cells of the CNS. They form the myelin sheath by wrapping their plasma membrane around axons. In addition to cell cycle activation, there is a downregulation of the expression of myelin-specific proteins, MBP and PLP [6, 7]. These molecular changes indicate that sublytic C5b-9 induces a progenitor-like phenotype in OLGs that may be critical for their survival in an inflammatory environment and important for regaining myelinating potential once the inflammation subsides [6]. Sublytic C5b-9 increases the expression of the voltage-gated potassium channel K(v)1.3, which controls C5b-9-induced Akt activation, providing another mechanism through which sublytic C5b-9 induces the cell cycle in OLGs [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
