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ERK1/ATF-2 signaling axis contributes to interleukin-1β-induced MMP-3 expression in dermal fibroblasts

Nanako Kitanaka1, Rei Nakano1,2, Manabu Sakai3

  • 1Laboratories of Veterinary Biochemistry, 3 Veterinary Internal Medicine, and 4Veterinary Radiotherapy, Nihon University College of Bioresource Sciences, Kameino, Fujisawa, Kanagawa, Japan.

Plos One
|September 20, 2019
PubMed

Insights

Interleukin-1β (IL-1β) induces matrix metalloproteinase-3 (MMP-3) expression in dermal fibroblasts via the ERK1/ATF-2 signaling pathway. This pathway is crucial for wound healing and tissue remodeling processes.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs) are key regulators of extracellular matrix (ECM) remodeling, essential for physiological and pathological processes like wound healing.
  • Interleukin-1β (IL-1β), a pro-inflammatory cytokine, upregulates MMP-3 expression in dermal fibroblasts, contributing to tissue repair mechanisms.

Purpose of the Study:

  • To elucidate the role of Activating Transcription Factor 2 (ATF-2) in IL-1β-induced MMP-3 expression in dermal fibroblasts.
  • To investigate the involvement of Mitogen-Activated Protein Kinase (MAPK) signaling, specifically Extracellular Signal-Regulated Kinases (ERK1/2), in ATF-2 activation and subsequent MMP-3 expression.

Main Methods:

  • Utilized siRNA to knockdown ATF-2, ERK1, and ERK2 expression in dermal fibroblasts.
  • Employed specific inhibitors (SBI-0087702 for ATF-2, FR180240 for ERK) to block signaling pathways.
  • Quantified MMP-3 mRNA expression and assessed ATF-2 and ERK1/2 phosphorylation levels following IL-1β stimulation.

Main Results:

  • IL-1β-induced MMP-3 mRNA expression was significantly reduced by ATF-2 knockdown or inhibition, indicating ATF-2's critical role.
  • IL-1β stimulation led to increased phosphorylation of both ATF-2 and ERK1/2, suggesting their activation in this pathway.
  • ERK inhibition and ERK1 knockdown, but not ERK2 knockdown, attenuated IL-1β-induced ATF-2 phosphorylation, highlighting ERK1's specific role in activating ATF-2.

Conclusions:

  • ATF-2 is a key mediator of IL-1β-induced MMP-3 expression in dermal fibroblasts.
  • The ERK1/ATF-2 signaling axis is essential for regulating MMP-3 expression in response to IL-1β, playing a significant role in tissue remodeling processes.

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