title: 5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1.
abstract: 5-Aminolevulinic acid (5-ALA) is the naturally occurring metabolic precursor of heme. Heme negatively regulates the Maf recognition element (MARE) binding- and repressing-activity of the Bach1 transcription factor through its direct binding to Bach1. Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide. These metabolites of heme protect against apoptosis, inflammation and oxidative stress. Monocytes and macrophages play a critical role in the initiation, maintenance and resolution of inflammation. Therefore, the regulation of inflammation in macrophages is an important target under various pathophysiological conditions. In order to address the question of what is responsible for the anti-inflammatory effects of 5-ALA, the induction of HO-1 expression by 5-ALA and sodium ferrous citrate (SFC) was examined in macrophage cell line (RAW264 cells). HO-1 expression induced by 5-ALA combined with SFC (5-ALA/SFC) was partially inhibited by MEK/ERK and p38 MAPK inhibitor. The NF-E2-related factor 2 (Nrf2) was activated and translocated from the cytosol to the nucleus in response to 5-ALA/SFC. Nrf2-specific siRNA reduced the HO-1 expression. In addition, 5-ALA/SFC increased the intracellular levels of heme in cells. The increased heme indicated that the inactivation of Bach1 by heme supports the upregulation of HO-1 expression. Taken together, our data suggest that the exposure of 5-ALA/SFC to RAW264 cells enhances the HO-1 expression via MAPK activation along with the negative regulation of Bach1.
authors: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Biomedical Sciences, Tokyo Denki University, Saitama, Japan.
authors: Yoshiaki
authors: Y
authors: Nishio
authors: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Masayuki
authors: M
authors: Fujino
authors: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Mingyi
authors: M
authors: Zhao
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Takuya
authors: T
authors: Ishii
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Masahiro
authors: M
authors: Ishizuka
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Hidenori
authors: H
authors: Ito
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Kiwamu
authors: K
authors: Takahashi
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Fuminori
authors: F
authors: Abe
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Motowo
authors: M
authors: Nakajima
authors: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors: Tohru
authors: T
authors: Tanaka
authors: Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan.
authors: Shigeru
authors: S
authors: Taketani
authors: Department of Biomedical Sciences, Tokyo Denki University, Saitama, Japan. Electronic address: yuki@mail.dendai.ac.jp.
authors: Yukitoshi
authors: Y
authors: Nagahara
authors: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: ri-k@ncchd.go.jp.
authors: Xiao-Kang
authors: XK
authors: Li
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D002460:Cell Line; D019343:Citric Acid; D004790:Enzyme Induction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D005296:Ferrous Compounds; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019343:Citric Acid; C016600:ferrous citrate; D000622:Aminolevulinic Acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 5-Aminolevulinic acid (ALA); Bach1; Heme; Heme oxygenase-1 (HO-1); Mitogen-activated protein kinases (MAPKs); Nrf2