Class I to III histone deacetylases differentially regulate inflammation-induced matrix metalloproteinase 9
Marin Poljak1, Ratana Lim, Gillian Barker
11Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.
Abstract:
Matrix metalloproteinase (MMP) 9 plays an important role in the degradation of the extracellular matrix in fetal membranes, and pathological activation of MMP-9 can lead to preterm birth. In nongestational tissues, modulation of histone deacetylases (HDACs) regulates MMP-9 expression. The aim of this study was to determine whether class I to III HDACs regulate MMP-9 expression and activity in primary amnion cells. Class I and II HDAC regulation of MMP-9 was assessed using the general class I and II HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), the class I HDACi MS-275, and the class II HDACi MC1568. Class III HDAC regulation of MMP-9 was assessed using the SIRT1 activators resveratrol and SRT1720 as well as SIRT1 small interfering RNA (siRNA). Primary amnion epithelial cells were incubated with 1 ng/mL interleukin (IL) 1β in the absence or presence of 0.3 μmol/L TSA, 5 μmol/L SAHA, 2.5 μmol/L MS-275, 2.5 μmol/L MC1568, 50 μmol/L resveratrol, or 10 μmol/L SRT1720 for 20 hours. We found that the class I and II HDACi TSA and SAHA and the class II HDACi MC1568 significantly decreased IL-β-induced MMP-9 gene and pro-MMP-9 expression in primary amnion cells. There was, however, no effect of the class I HDACi MS-275 on IL-β-induced MMP-9 expression. On the other hand, inhibition of class III HDAC SIRT1 using siRNA significantly augmented IL-1β-induced MMP-9, and SIRT1 activation using resveratrol and SRT1720 inhibited IL-1β-induced MMP-9 expression. In summary, class I to III HDACs differentially regulate inflammation-induced MMP-9 expression in primary amnion cells.
Insights
Histone deacetylases (HDACs) regulate matrix metalloproteinase-9 (MMP-9) in amnion cells. Class I/II HDAC inhibition decreased MMP-9, while class III HDAC SIRT1 inhibition increased it, impacting preterm birth risk.
Area of Science:
- Reproductive biology
- Molecular endocrinology
- Biochemistry
Background:
- Matrix metalloproteinase-9 (MMP-9) is crucial for extracellular matrix degradation in fetal membranes.
- Pathological MMP-9 activation is linked to preterm birth.
- Histone deacetylases (HDACs) are known regulators of MMP-9 expression in non-gestational tissues.
Purpose of the Study:
- To investigate the role of class I, II, and III HDACs in regulating MMP-9 expression and activity in primary amnion cells.
- To determine how specific HDAC inhibitors and activators affect inflammation-induced MMP-9 in amnion cells.
Main Methods:
- Primary amnion epithelial cells were treated with interleukin-1β (IL-1β) to induce inflammation.
- Cells were co-treated with various HDAC inhibitors (TSA, SAHA, MS-275, MC1568) and SIRT1 modulators (resveratrol, SRT1720, SIRT1 siRNA).
- MMP-9 gene and pro-MMP-9 expression levels were quantified.
Main Results:
- Class I and II HDAC inhibitors (TSA, SAHA) and the class II inhibitor (MC1568) significantly reduced IL-1β-induced MMP-9 expression.
- The class I inhibitor (MS-275) showed no significant effect on IL-1β-induced MMP-9 expression.
- SIRT1 activation (resveratrol, SRT1720) inhibited IL-1β-induced MMP-9, while SIRT1 inhibition (siRNA) augmented it.
Conclusions:
- Class I, II, and III HDACs differentially regulate inflammation-induced MMP-9 expression in primary amnion cells.
- Targeting specific HDACs may offer a therapeutic strategy to modulate MMP-9 activity and potentially prevent preterm birth.
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