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.
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.


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.
Ogborne
Richard M
RM
MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, CB1 9NL, UK.
Rushworth
Stuart A
SA
O'Connell
Maria A
MA
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D005799:Genes, Dominant; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007938:Leukemia; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements / Q000502:physiology; D008063:Thioctic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D008063:Thioctic Acid; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases