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MicroRNA-142-3p and let-7g Negatively Regulates Augmented IL-6 Production in Neonatal Polymorphonuclear Leukocytes
Hsin-Chun Huang1,2, Hong-Ren Yu1, Te-Yao Hsu3
1Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Kaohsiung, Taiwan.
Abstract:
Neonatal PMN are qualitatively impaired in functions, yet they frequently reveal augmented inflammatory reactions during sepsis. Here, we hypothesized that PMN from newborns produce more IL-6 than those from adults under LPS stimulation, in which transcriptional or posttranscriptional regulation is involved in the altered expression. We found that neonatal PMN produced significantly higher IL-6 mRNA and protein than adult PMN. The higher IL-6 expression was not related to transcriptional but posttranscriptional regulation as the IL-6 expression was affected by the addition of cycloheximide but not actinomycin. To examine whether miRNA was involved in the IL-6 regulation of neonatal PMN, we surveyed differential displays of miRNAs that could potentially regulate IL-6 expression before and after LPS stimulation. Four miRNAs: hsa-miR-26a, hsa-miR-26b, hsa-miR-142-3p and hsa-let 7g decreased or increased after LPS treatment for 4 h. Further validation by qRT-PCR identified miR-26b, miR-142-3p and let-7g significantly changed in neonatal PMN after LPS stimulation. The functional verification by transfection of miR-142-3p and let-7g precursors into neonatal PMN significantly repressed the IL-6 mRNA and protein expression, suggesting that miR-142-3p and let-7g negatively regulate IL-6 expression in neonatal PMN. Modulation of miRNA expression may be used to regulate IL-6 production in newborns with altered inflammatory reactions.
Insights
Neonatal neutrophils produce more IL-6 during sepsis due to posttranscriptional regulation. Specific microRNAs, miR-142-3p and let-7g, negatively control this IL-6 production in newborns.
Area of Science:
- Immunology
- Neonatal Research
- Molecular Biology
Background:
- Neonatal neutrophils (PMN) exhibit impaired functions but heightened inflammatory responses in sepsis.
- Understanding the mechanisms behind neonatal inflammatory reactions is crucial for effective treatment.
Purpose of the Study:
- To investigate the hypothesis that neonatal PMN produce more IL-6 than adult PMN under LPS stimulation.
- To determine if transcriptional or posttranscriptional regulation, including microRNA (miRNA) involvement, underlies altered IL-6 expression in neonatal PMN.
Main Methods:
- Comparison of IL-6 mRNA and protein levels in neonatal versus adult PMN after LPS stimulation.
- Assessment of transcriptional vs. posttranscriptional regulation using cycloheximide and actinomycin.
- miRNA profiling (qRT-PCR) to identify differentially expressed miRNAs.
- Functional validation of miRNA roles via precursor transfection and subsequent IL-6 expression analysis.
Main Results:
- Neonatal PMN demonstrated significantly higher IL-6 mRNA and protein production compared to adult PMN.
- IL-6 overproduction was attributed to posttranscriptional regulation, not transcriptional.
- LPS stimulation altered the expression of specific miRNAs (miR-26b, miR-142-3p, let-7g) in neonatal PMN.
- Transfection of miR-142-3p and let-7g precursors suppressed IL-6 expression in neonatal PMN, indicating their negative regulatory role.
Conclusions:
- Neonatal PMN exhibit elevated IL-6 production via posttranscriptional mechanisms.
- miR-142-3p and let-7g act as negative regulators of IL-6 expression in neonatal PMN.
- Modulating miRNA expression presents a potential therapeutic strategy for managing inflammatory responses in newborns with sepsis.
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