Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective properties.
Its role in effecting a deactivated state of oxidized low-density lipoprotein (oxLDL)-generated foam cell macrophages (FCMs), a prevailing cellular phenotype of atherosclerotic lesions, has not been investigated yet.
In this study RAW264.7- or mouse peritoneal macrophage-derived FCMs showed reduced mRNA expression of proinflammatory cytokines such as IL-1β and IL-6 and an attenuated production of reactive oxygen species (ROS), as analyzed by hydroethidine in response to lipopolysaccharide (LPS) and compared to LPS-treated control macrophages.
In peritoneal FCMs from Nrf2-/- mice (C57BL/6J), the LPS-induced proinflammatory response was restored. OxLDL induced heme oxygenase (HO)-1, which was Nrf2-dependent, and inhibition of HO-1 activity in FCMs using zinc protoporphyrin-IX allowed the cells to regain a proinflammatory phenotype. Mechanistically, oxLDL attenuated ROS-dependent activation of CCAAT/enhancer binding protein (C/EBP) family members in FCMs, thereby reducing cytokine expression. Thus, in FCMs the Nrf2/HO-1 axis intervenes in LPS signaling. ROS production is impaired, C/EBP transactivation is reduced, and consequently the expression of proinflammatory mediators is attenuated, thereby shaping a desensitized FCM phenotype.
This macrophage phenotype may be important for the progression of atherosclerosis.
Fecha de publicación
RevistaFree radical biology & medicine
Free Radic Biol Med (1873-4596)
Temas de la revista
Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University, 60590 Frankfurt, Germany.
Referencia de entrega
Free Radic Biol Med. 2011 May;50(10):1382-91
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