Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes.
Heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. Our previous studies have demonstrated that bradykinin (BK) induces the expression of several inflammatory proteins, including matrix metalloproteinase-9 and COX-2, via mitogen-activated protein kinases and nuclear factor-κB (NF-κB) in rat brain astrocytes (RBA-1). However, the molecular mechanisms underlying BK-induced HO-1 expression in RBA-1 cells remain poorly defined. Here we demonstrated that BK induced HO-1 expression and enzymatic activity via a B(2) BK receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream molecules NF-κB and c-Jun, respectively. The c-Fos, an activator protein 1 (AP-1) subunit, was upregulated by activation of NF-κB and c-Jun, which bound to HO-1 promoter and thereby turned on transcription of HO-1 gene. The rat HO-1 promoter containing a putative AP-1 cis-binding site was identified as a crucial domain linking to BK action. Taken together, these results suggested that in RBA-1 cells, activation of ERK/NF-κB and JNK/c-Jun cascades by a Nox/ROS-dependent event enhancing c-Fos/AP-1 activity is essential for HO-1 upregulation and activation induced by BK. Moreover, ROS-dependent NF-E2-related factor 2 activation also contributes to HO-1 induction by BK in astrocytes.
Hsieh
Hsi-Lung
HL
Division of Basic Medical Sciences, Department of Nursing, Chang Gung Institute of Technology , Tao-Yuan, Taiwan.
Wang
Hui-Hsin
HH
Wu
Cheng-Ying
CY
Yang
Chuen-Mao
CM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D051547:Heme Oxygenase-1; D001920:Bradykinin