Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation.

Abstract

Gram-negative sepsis is the most common cause of the adult respiratory distress syndrome (ARDS). Lipopolysaccharide (LPS) when administered in vivo produces pathophysiologic changes similar to those seen in ARDS. The pathogenesis of these changes is mediated in part by oxidative stress. We demonstrate that LPS induces high mRNA levels of the stress-inducible gene heme oxygenase-1 (HO-1) in the rat lung. Increased HO-1 mRNA levels correlate with increased HO-1 protein and enzyme activity. Immunohistochemical analyses of lung tissues from rats treated with LPS reveal abundant HO-1 expression in inflammatory and bronchoalveolar epithelial cells. We further examined the molecular regulation of HO-1 gene expression after exposure of RAW 264.7 macrophage cells to LPS in vitro. These cells respond to LPS with increased HO-1 mRNA expression and HO-1 gene transcription. Transcriptional activation of the mouse HO-1 gene by LPS is mediated by a 5' distal enhancer fragment located approximately 4 kbp upstream from the transcription site. Electrophoretic mobility shift assays show increased activator protein-1 (AP-1) binding activity in RAW 264.7 cells after LPS treatment. Mutation of the AP-1 binding site in this enhancer fragment completely abolishes HO-1 gene activation while mutation of CCAAT/enhancer-binding protein (C/EBP) binding site exerts negligible effect, suggesting that the AP-1 family of transcription factors plays a critical role in regulating HO-1 gene activation following LPS treatment. Furthermore, upstream phosphorylation events modulate this AP-1-dependent expression of the HO-1 gene after LPS treatment.

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

“…HO-3 is the least understood and may be a pseudogene, and at least in the rat, it has been suggested that there is no functional HO-3 gene (12). HO-1 can be induced by a variety of agents causing oxidative stress including heavy metals, cytokines, hormones, endotoxin, and heat shock (1,3,6,17,25). Emerging body of evidence indicates that HO-1, besides its role in heme degradation, serves as a key biological molecule in the adaptation response and defense against oxidative stresses, and it provides cytoprotection in a variety of in vivo and in vitro models of cellular and tissue inflammation and injury (33).…”

TGF-β1stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells

“…Although heme is the major substrate of HO-1, a wide variety of agents, including heavy metals, cytokines, hormones, endotoxin, and heat shock, has been identified as strong inducers of HO-1 expression (1,5,24,33). HO-1 is highly induced by various inflammatory stimulants and agents that cause oxidative stress, such as hydrogen peroxide, glutathione depletors, UV radiation, hyperoxia, and ischemia-reperfusion injury (5,18,22).…”

“…HO-1 expression responds to stimulation by a number of chemical and physical effectors, including its physiological substrate heme, as well as heavy metals, ultraviolet radiation, oxidants, nitric oxide, thiol-reactive substances, and hyperoxic or hypoxic states (1,4,24). Furthermore, HO-1 responds to a number of cytokines, hormones, and related sub-stances, including proinflammatory mediators such as tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), and bacterial lipopolysaccharide, the thrombopoietic cytokine IL-11, and growth factors, such as plateletderived growth factor and TGF-␤ 1 (5,16,21,24).…”

Effective suppression of nitric oxide production by HX106N through transcriptional control of heme oxygenase-1

“…16,18,27,28 Therefore, the effect of HX106N on the activation of Nrf2 and AP-1 was examined by assessing the nuclear accumulation of Nrf2 and c-Jun, a major component of the AP-1 family. BV-2 cells were treated with 1 mg/mL HX106N, and the nuclear proteins were extracted at various time points, followed by Western blot analysis to determine the levels of these two transcription factors.…”