TY - JOUR
T1 - alpha-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells
AU - Ogborne, R. M.
AU - Rushworth, S. A.
AU - O'Connell, M. A.
PY - 2005
Y1 - 2005
N2 - Objective - Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, plays a protective role in the vascular system. HO-1 induction inhibits cytokine production in macrophages. Antioxidants induce HO-1 expression in various cell types. alpha-lipoic acid (ALA), a thiol-containing dietary antioxidant, exhibits protective effects in vascular disease and induces anti-inflammatory effects in monocytes. This study examined the effects of ALA on HO-1 expression in human monocytic cells. Methods and Results - ALA time and dose-dependently induced HO-1 mRNA expression in THP-1 cells, with peak expression at 4 hours and returning to baseline by 24 hours. This correlated with an increase in HO-1 protein expression. ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2 - related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element ( ARE) by 30 minutes. A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66%. Pretreatment with SB203580, a p38 mitogen-activated protein kinase inhibitor, reduced ALA-induced HO-1 mRNA expression by 75% and inhibited ALA-induced Nrf2 binding to the HO-1 ARE. Conclusions - These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.
AB - Objective - Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, plays a protective role in the vascular system. HO-1 induction inhibits cytokine production in macrophages. Antioxidants induce HO-1 expression in various cell types. alpha-lipoic acid (ALA), a thiol-containing dietary antioxidant, exhibits protective effects in vascular disease and induces anti-inflammatory effects in monocytes. This study examined the effects of ALA on HO-1 expression in human monocytic cells. Methods and Results - ALA time and dose-dependently induced HO-1 mRNA expression in THP-1 cells, with peak expression at 4 hours and returning to baseline by 24 hours. This correlated with an increase in HO-1 protein expression. ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2 - related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element ( ARE) by 30 minutes. A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66%. Pretreatment with SB203580, a p38 mitogen-activated protein kinase inhibitor, reduced ALA-induced HO-1 mRNA expression by 75% and inhibited ALA-induced Nrf2 binding to the HO-1 ARE. Conclusions - These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.
U2 - 10.1161/01.ATV.0000183745.37161.6e
DO - 10.1161/01.ATV.0000183745.37161.6e
M3 - Article
SN - 1079-5642
VL - 25
SP - 2100
EP - 2105
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 10
ER -