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Enhanced expression of MafB inhibits macrophage apoptosis induced by cigarette smoke exposure
Jun-Ichi Machiya1, Yoko Shibata, Keiko Yamauchi
1Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Abstract:
In the lungs of smokers, oxidative stress rises due to increase of free radicals and oxidants, including lipid peroxide (LPO). The functions of alveolar macrophages (AMs) are altered in such an environment, and their survival is prolonged against toxicities of cigarette smoke (CS) by an unknown mechanism. Whereas functions of AMs are potentially regulated by various transcriptional factors, their expressions and roles in smoking individuals have not been elucidated. Therefore, we investigated their expressions using murine model of CS exposure. Eight-week-old male B6C3F1 mice were whole-bodily exposed to CS (2 cigarettes/mouse/day, 5 d/wk) for 6 mo. Development of pulmonary emphysema in 6-mo CS-exposed mice was confirmed by a morphometric analysis. Among the transcriptional factors investigated, only MafB was upregulated in AMs from CS-exposed mice. DNA binding capacity of MafB for Maf recognition element was also increased in AMs from those mice. LPO was increased significantly in the lungs of CS-exposed mice. Because the end product of LPO, 4-hydroxy-2-nonenal, enhanced MafB expression and its transcriptional activity in a cultured macrophage cell line, LPO-related oxidative stress was suggested to be involved in the mechanism of MafB expression in CS-exposed lung. Furthermore, we established a macrophage cell line that can overexpress MafB and thereby clarify the role of MafB. Forced expression of MafB heightened cell viability and attenuated the occurrence of apoptosis in cells treated with CS-extract. These results suggest that enhanced MafB expression by oxidative stress inhibits AM cell death and prolongs their survival in the CS-exposed lung.
Insights
Oxidative stress from smoking increases lipid peroxide (LPO) in lungs. This elevates MafB expression in alveolar macrophages (AMs), prolonging their survival against cigarette smoke (CS) toxicity.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Toxicology
Background:
- Smokers' lungs experience increased oxidative stress and altered alveolar macrophage (AM) functions.
- The mechanisms behind prolonged AM survival in response to cigarette smoke (CS) are not fully understood.
- The roles of transcriptional factors in AMs of smokers remain largely unelucidated.
Purpose of the Study:
- To investigate the expression of transcriptional factors in AMs from a murine model of CS exposure.
- To elucidate the role of MafB in AM survival under conditions of oxidative stress induced by CS.
Main Methods:
- Mice were exposed to CS for 6 months to induce pulmonary emphysema.
- Expression and DNA binding capacity of transcriptional factors in AMs were analyzed.
- Macrophage cell lines were used to study the effects of lipid peroxide (LPO) and MafB expression.
Main Results:
- MafB was significantly upregulated in AMs of CS-exposed mice, with increased DNA binding capacity.
- Lipid peroxide (LPO) levels were elevated in the lungs of CS-exposed mice.
- 4-hydroxy-2-nonenal, an LPO product, enhanced MafB expression and activity in cultured macrophages.
- Overexpression of MafB in macrophages increased cell viability and reduced apoptosis induced by CS extract.
Conclusions:
- CS-induced oxidative stress, specifically LPO, upregulates MafB expression in lung AMs.
- Enhanced MafB expression contributes to the prolonged survival of AMs by inhibiting apoptosis in the CS-exposed lung.
- MafB may represent a novel therapeutic target for mitigating CS-induced lung damage.
