A Novel Role for SIRT3 in Regulating Mediators Involved in the Terminal Pathways of Human Labor and Delivery

Abstract

Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators has been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2, and SIRT6 in regulating inflammation-induced prolabor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5, and SIRT7 expression in human myometrium. Functional studies were also used to investigate the effect of small interfering RNA (siRNA) knockdown of SIRTs in regulating inflammation-induced prolabor mediators. Western blot analysis and qRT-PCR were used to determine SIRT3, SIRT4, SIRT5, and SIRT7 mRNA and protein expression in human myometrium. Small interfering RNA knockdown of SIRT3 in myometrial primary cells determined its role in response to inflammatory stimuli IL1B and TNF. SIRT3 mRNA and protein expression levels were significantly lower in term laboring myometrium compared with term nonlaboring myometrium. There was no effect of labor on SIRT4, SIRT5 or SIRT7 protein expression. The pro-inflammatory cytokines IL1B and TNF significantly decreased levels of SIRT3 mRNA and protein expression. SIRT3 knockdown by siRNA significantly augmented IL1B- and TNF-stimulated IL6, CXCL8, and CCL2 mRNA expression and release; PTGS2 mRNA expression and subsequent PGF2alpha release; the mRNA expression and secretion of the adhesion molecule ICAM1 and the extracellular matrix remodeling enzyme MMP9; and nuclear factor kappa B1 (NFkappaB1) transcriptional activity. In human myometrium, SIRT3 expression decreases with term labor and regulates the mediators involved in the terminal effector pathways of human labor and delivery through the NFkappaB1 pathway.

Regulation of Sirtuin 3-Mediated Deacetylation of Cyclophilin D Attenuated Cognitive Dysfunction Induced by Sepsis-Associated Encephalopathy in Mice

“…SIRT3 activation plays a protective role against mitochondrial damage in the kidney by attenuating oxidative stress, inhibiting the NRLP3 inflammasome, attenuating ROS production, and downregulating IL-1β (Zhao et al 2016 ). SIRT3 deletion increases the expressions of IL-1β, TNF, and IL-6 in the inflammation (Lim et al 2016 ). It has been proven that SIRT3 decreased in neurodegeneration such as Alzheimer’s disease (Jęśko et al 2016 ).…”

Roles of Progesterone Receptor Membrane Component 1 in Oxidative Stress—Induced Aging in Chorion Cells

“…23,25 Recently, SIRT3 was found to be associated with labor in human myometrium. 26 Due to the novelty of SIRT3, its role remains unknown in fetal membranes.…”

IRF5 is increased in labouring myometrium and regulates pro-labour mediators

“…Much research over the last decade has been focussed on the identification of inflammatory molecules that can be targeted to mitigate the inflammatory response associated with preterm labour. In addition to NF-κB, we have identified a number of regulators of inflammation including A20 (Lappas 2017a), Kruppel-like factor 5 (KLF5) (Lappas 2015), sirtuins (SIRTs) (Lappas et al 2011, Lim et al 2013b, 2016a, Poljak et al 2014 and forkhead box O (FOXO) proteins (Lim et al 2013a). Whether IRF5 may interact with these signalling proteins to regulate pro-labour mediators is not known and an avenue for further research.…”