Enhanced Expression of MafB Inhibits Macrophage Apoptosis Induced by Cigarette Smoke Exposure

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.

Overexpression of Mafb in Podocytes Protects against Diabetic Nephropathy

“…Mafb expression has been shown to confer antiapoptotic effects in myeloma and macrophage cell lines. 24,41 In summary, we showed in the present study that Mafb might play a protective role in diabetic nephropathy. This effect is regulated through slit-diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes.…”

MafB promotes atherosclerosis by inhibiting foam-cell apoptosis

“…These observations imply that MafB might play a pathogenic role in the development of atherosclerotic lesions. Moreover, MafB expressed in alveolar macrophages participates in the pathophysiology of chronic obstructive pulmonary disease that is related to cigarette smoking 30 .…”

Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation

“…Cigarette smoke, which contains numerous reactive oxygen species (ROS) and cytotoxic by-products of oxidation reactions (25), including acrolein and hydroperoxides, induces DNA damage (26), resulting in cell growth inhibition and cellular senescence (27). The role of redox regulation and balance in cigarette smoke extract (CSE)-induced cell death has been extensively studied by using in vitro models (28)(29)(30)(31)(32); however, little is known about the role of redox regulation in cellular senescence. In this study, we evaluated a possible link between CSE and WRN protein regulation.…”