Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells.
Heme iron exacerbates oxidant damage by catalyzing the production of free radicals. Heme oxygenase is the rate-limiting enzyme involved in heme catabolism. An inducible form of heme oxygenase, heme oxygenase-1 (HO-1), is upregulated in oxidant and inflammatory settings, and recent work suggests that HO-1 induction may serve a protective function against oxidant injury. The ability of the endogenous inflammatory mediators, interleukin (IL)-1 alpha, tumor necrosis factor-alpha (TNF-alpha), and IL-6, to enhance HO-1 expression in cultured human endothelial cells was examined in this study. HO-1 mRNA and protein expression were upregulated by IL-1 alpha and TNF-alpha exposure but not by IL-6. Induction of HO-1 mRNA by IL-1 alpha and TNF-alpha occurred in a concentration- and time-dependent fashion, with maximal expression occurring by 4 h for both cytokines. Induction depended on protein synthesis and occurred at the transcriptional level. Inhibition of the AP-1 transcription factor with curcumin decreased the cytokine induction of HO-1 mRNA, suggesting the involvement of this transcription factor in cytokine signaling of HO-1. The results of this study indicate that the endogenous inflammatory cytokines IL-1 alpha and TNF-alpha induce HO-1 in endothelial cells, providing further evidence that HO-1 may be an important cellular response to inflammatory stress.
Terry
C M
CM
Department of Pharmacology and Toxicology, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Clikeman
J A
JA
Hoidal
J R
JR
Callahan
K S
KS
D015153:Blotting, Western; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D015850:Interleukin-6; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D006419:Heme Oxygenase (Decyclizing)