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MAPK and JAK-STAT signaling pathways are involved in the oxidative stress-induced decrease in expression of
Sang-Kyu Park1, Mary K Dahmer, Michael W Quasney
1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53201, USA.
Summary
Hydrogen peroxide (H(2)O(2)) alters surfactant protein gene expression in lung cells, decreasing SP-A, SP-B, and ABCA3 while increasing SP-D. Antioxidants and pathway inhibitors reveal involvement of TTF-1, MAPK, and JAK-STAT signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Oxidative stress, driven by reactive oxygen species (ROS), disrupts cellular redox balance and contributes to chronic inflammatory diseases.
- Surfactant proteins (SP-A, SP-B, SP-D) and ABCA3 are crucial for lung function and surfactant homeostasis.
- The impact of oxidative stress on the expression of these key lung genes is not fully understood.
Purpose of the Study:
- To investigate the effects of hydrogen peroxide (H(2)O(2)) on the mRNA levels of surfactant proteins (SP-A, SP-B, SP-D) and ABCA3 in human pulmonary lung epithelial cells.
- To elucidate the signaling pathways and transcription factors involved in H(2)O(2)-mediated gene regulation.
- To determine the role of antioxidants in mitigating H(2)O(2)-induced changes in gene expression.
Main Methods:
- Human pulmonary lung epithelial cells were treated with varying concentrations of H(2)O(2).
- mRNA levels of SP-A, SP-B, SP-D, and ABCA3 were quantified using quantitative PCR.
- Cells were pretreated with antioxidants (N-acetyl-L-cysteine, catalase) and specific pathway inhibitors (U0126, SB203580, AG-490) to assess their effects.
- Thyroid transcription factor-1 (TTF-1) DNA binding activity and protein expression were analyzed.
- MAPK and JAK-STAT signaling pathway activation was assessed via immunoblotting.
Main Results:
- H(2)O(2) significantly decreased SP-A, SP-B, and ABCA3 mRNA levels, while increasing SP-D mRNA levels.
- Antioxidant pretreatment blocked H(2)O(2)-induced changes in gene expression.
- H(2)O(2) reduced TTF-1 DNA binding activity, potentially via decreased TTF-1 protein expression.
- MAPK (ERK1/2, p38) and JAK-STAT (STAT3) signaling pathways were activated by H(2)O(2) and involved in the regulation of SP-A and SP-B gene expression.
Conclusions:
- Hydrogen peroxide significantly modulates the expression of key surfactant protein genes and ABCA3 in lung epithelial cells.
- The observed gene expression changes are mediated by oxidative stress and involve the transcription factor TTF-1.
- MAPK and JAK-STAT signaling pathways play critical roles in H(2)O(2)-induced alterations of SP-A and SP-B gene expression, highlighting potential therapeutic targets for oxidative stress-related lung diseases.
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