Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition.
BACKGROUND
Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood.


OBJECTIVE
The principal goal of the work was to examine the inflammatory genomic profile of human decidual cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of decidual stromal cells.


METHODS
The effects of interleukin-1β exposure on mature microRNA expression were tested in human decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time-polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions.


RESULTS
Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate < 0.1), respectively, including induction of numerous cytokines, chemokines, and other inflammatory mediators. Whereas this transcriptional response included marked changes in several microRNA gene loci, the pool of fully processed, mature microRNA was comparatively stable following a cytokine challenge. Of a total of 6 mature microRNAs identified as being differentially expressed by NanoString profiling, 2 (miR-146a and miR-155) were validated by quantitative real time-polymerase chain reaction. Using complementary bioinformatics approaches, activation of several inflammatory transcription factors could be inferred downstream of interleukin-1β based on the overall transcriptional response. Further analysis revealed that miR-146a and miR-155 both target genes involved in inflammatory signaling, including Toll-like receptor and mitogen-activated protein kinase pathways.


CONCLUSIONS
Stimulation of decidual cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance.
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH.
Sherrine A
SA
Ibrahim
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH.
William E
WE
Ackerman
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH.
Taryn L
TL
Summerfield
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH.
Charles J
CJ
Lockwood
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH.
Frederick
F
Schatz
Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, College of Engineering, The Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, Wexner Medical Center and College of Medicine, and Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH. Electronic address: kniss.1@osu.edu.
Douglas A
DA
Kniss
D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D003656:Decidua / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D035683:MicroRNAs / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D036801:Parturition / Q000235:genetics* / Q000276:immunology; D011247:Pregnancy; D012333:RNA, Messenger / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051193:Toll-Like Receptors / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; D053583:Interleukin-1beta; D035683:MicroRNAs; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases
inflammation; microribonucleic acid; preterm birth; systems biology; transcription factor