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5-Aza-2'-deoxycytidine and interleukin-1 cooperate to regulate matrix metalloproteinase-3 gene expression
Julie Couillard1, Pierre-Olivier Estève, Sriharsa Pradhan
1INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.
Abstract:
Members of the matrix metalloproteinase (MMP) family of enzymes play a critical role in extracellular matrix remodeling in a number of normal and pathologic processes. Accordingly, activation of MMP gene expression is tightly regulated at the level of transcription by specific transcription factors, most notably following exposure to inflammatory cytokines. Recent studies with 5-aza-2'-deoxycytidine (5-aza-dC), a specific DNA methylase inhibitor, also suggest that epigenetic processes contribute to the regulation of MMP expression. Although inflammation-related aberrant patterns of DNA methylation have been described, a mechanistic link between inflammation and epigenetic alterations in the control of MMP expression remains unclear. Here, we provide evidence that increased MMP-3 expression by 5-aza-dC is modulated by interleukin-1 (IL-1). More specifically, we found that stimulation with IL-1, but not with IL-6 or TNFα, significantly increased the hypomethylation status of the MMP-3 promoter to a level similar to that found in dnmt1/dnmt3b-deficient HCT116 (DKO) cells. Furthermore, we showed that increased MMP-3 expression by 5-aza-dC was associated with increased expression and activity of specific transcription factors known to regulate MMP-3 expression. In fact, treatment with 5-aza-dC was obligatory for some transcription factors to trigger an increase in MMP-3 expression, such as Ap-1. In contrast, CCAAT enhancer-binding proteins and E-twenty six were capable of inducing MMP-3 alone. Overall, these findings provide a novel perspective of the collaborative role of 5-aza-dC and inflammatory cytokines with specific transcription factors that are normally involved in MMP-3 expression.
Insights
This study reveals how interleukin-1 (IL-1) and DNA methylase inhibitors like 5-aza-2'-deoxycytidine (5-aza-dC) interact to increase matrix metalloproteinase-3 (MMP-3) expression, highlighting epigenetic regulation in inflammation.
Area of Science:
- Molecular Biology
- Epigenetics
- Cellular Biology
Background:
- Matrix metalloproteinases (MMPs) are crucial for extracellular matrix remodeling in various physiological and pathological conditions.
- MMP gene expression is regulated by transcription factors and inflammatory cytokines, with recent evidence suggesting epigenetic involvement.
- The precise link between inflammation, epigenetic modifications, and MMP expression control remains incompletely understood.
Purpose of the Study:
- To investigate the mechanistic link between inflammation, DNA methylation, and the expression of matrix metalloproteinase-3 (MMP-3).
- To elucidate the role of interleukin-1 (IL-1) in modulating MMP-3 expression in conjunction with epigenetic regulators.
Main Methods:
- Utilized 5-aza-2 -deoxycytidine (5-aza-dC), a DNA methylase inhibitor, to study epigenetic effects on MMP-3 expression.
- Stimulated cells with various inflammatory cytokines, including IL-1, IL-6, and TNFα, to assess their impact on MMP-3 promoter methylation.
- Analyzed the expression and activity of transcription factors (Ap-1, C/EBP, Ets) involved in MMP-3 regulation.
Main Results:
- Interleukin-1 (IL-1) stimulation significantly increased MMP-3 promoter hypomethylation, similar to that observed in DNA methyltransferase-deficient cells.
- 5-aza-dC treatment enhanced MMP-3 expression, correlating with increased activity of specific transcription factors like Ap-1.
- Certain transcription factors, such as CCAAT enhancer-binding proteins and E-twenty six, could induce MMP-3 expression independently.
Conclusions:
- Findings demonstrate a collaborative role between 5-aza-dC, IL-1, and specific transcription factors in regulating MMP-3 expression.
- This study provides novel insights into the epigenetic mechanisms underlying inflammation-driven MMP expression.
- The results highlight the intricate interplay between epigenetic modifications and inflammatory signaling in controlling extracellular matrix remodeling.
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