title: 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 PGF2alpharelease; 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.
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.|Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Ratana
authors.initials: R
authors.lastname: Lim
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.|Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Barker
authors.affiliation: Department of Obstetrics and Gynecology, Division of Perinatal Research, The University of Texas Medical Branch at Galveston, Galveston, Texas.|Department of Clinical Medicine and Obstetrics and Gynecology, Aarhus University, Aarhus, Denmark.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia mlappas@unimelb.edu.au.|Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
mesh_terms: D000328:Adult; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D036861:Delivery, Obstetric; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007743:Labor, Obstetric / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009215:Myometrium / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D034741:RNA, Small Interfering; D056566:Sirtuin 3 / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D047929:Term Birth / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; C573420:ICAM1 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C510661:SIRT7 protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; C466093:SIRT3 protein, human; C525357:SIRT4 protein, human; C508544:SIRT5 protein, human; D056566:Sirtuin 3; D037761:Sirtuins
keywords: SIRT3; human labor; inflammation; myometrium