TNF-α and IL-1α induce heme oxygenase-1 via protein kinase C, Ca2+, and phospholipase A2 in endothelial cells

被引:133
作者
Terry, CM
Clikeman, JA
Hoidal, JR
Callahan, KS
机构
[1] Univ Utah, Dept Pharmacol & Toxicol, Div Pulm, Salt Lake City, UT 84132 USA
[2] Univ Utah, Dept Internal Med, Salt Lake City, UT 84132 USA
[3] Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 1999年 / 276卷 / 05期
关键词
cytokine; phorbol; 12-myristate; 13-acetate; phosphatase; protein kinase C downregulation; protein kinase C isoforms; tumor necrosis factor-alpha; interleukin-1; alpha;
D O I
10.1152/ajpheart.1999.276.5.H1493
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Heme oxygenase-1 (HO-1), an enzyme important in protection against oxidant stress, is induced in human vascular endothelial cells by the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha). However, the signaling mediators that regulate the induction are not known. This study examined the involvement of protein kinase C (PKC), phospholipase A(2) (PLA(2)), calcium, and oxidants in cytokine induction of HO-1. Acute exposure to the PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated HO-1 mRNA. However, prolonged exposure, which downregulates most PKC isoforms, blocked induction of HO-1 mRNA by IL-1 alpha and TNF-alpha. Additionally, the phosphatase inhibitors okadaic acid and calyculin enhanced cytokine induction of HO-1. Mepacrine, a PLA(2) inhibitor, prevented HO-1 induction by cytokine, suggesting a role for arachidonate, the product of PLA(2) hydrolysis of phospholipids, in HO-1 expression. The intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) blocked cytokine induction of HO-1. Paradoxically, the calcium ionophore A-23187 prevented HO-1 induction by cytokine but not by PMA. Finally, the oxidant scavenger N-acetylcysteine inhibited HO-1 induction by cytokines. These results demonstrate that TNF-alpha and IL-1 alpha induction of HO-1 requires PKC-mediated phosphorylation and PLA(2) activation as well as oxidant generation.
引用
收藏
页码:H1493 / H1501
页数:9
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