Terry C M, Clikeman J A, Hoidal J R, Callahan K S
Department of Pharmacology and Toxicology, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Am J Physiol. 1998 Mar;274(3):H883-91. doi: 10.1152/ajpheart.1998.274.3.H883.
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.
血红素铁通过催化自由基的产生加剧氧化损伤。血红素加氧酶是参与血红素分解代谢的限速酶。血红素加氧酶-1（HO-1）是血红素加氧酶的一种可诱导形式，在氧化和炎症环境中上调，最近的研究表明，HO-1的诱导可能对氧化损伤起到保护作用。本研究检测了内源性炎症介质白细胞介素（IL）-1α、肿瘤坏死因子-α（TNF-α）和IL-6在培养的人内皮细胞中增强HO-1表达的能力。IL-1α和TNF-α暴露可上调HO-1 mRNA和蛋白表达，但IL-6无此作用。IL-1α和TNF-α对HO-1 mRNA的诱导呈浓度和时间依赖性，两种细胞因子在4小时时均出现最大表达。诱导依赖于蛋白质合成，且发生在转录水平。用姜黄素抑制AP-1转录因子可降低细胞因子对HO-1 mRNA的诱导，提示该转录因子参与了HO-1的细胞因子信号传导。本研究结果表明，内源性炎症细胞因子IL-1α和TNF-α可在内皮细胞中诱导HO-1，进一步证明HO-1可能是细胞对炎症应激的重要反应。
