Chen Yen-Chou, Shen Shing-Chuan, Lee Woan-Ruoh, Lin Hui-Yi, Ko Ching-Huai, Lee Tony J F
Graduate Institute of Pharmacognosy Science, Taipei Medical University, Taiwan.
J Cell Biochem. 2002;86(2):331-9. doi: 10.1002/jcb.10230.
Induction of heme oxygenase (HO)-1 during inflammation has been demonstrated in many cell types, but the contribution of inflammatory molecules nitric oxide (NO) and prostaglandin E(2) (PGE(2)) has remained unresolved. Here we show that NO donors including sodium nitroprusside (SNP) and spermine nonoate (SP-NO), and PGE(2) significantly stimulate HO-1 expression in RAW264.7 macrophages, associated with alternative induction on NO and PGE(2) in medium, respectively. NO donors also show the inductive effect on cyclo-oxygenase 2 protein and PGE(2) production. In the presence of lipopolysaccharide and interferon-gamma (LPS/IFN-gamma), HO-1 protein was induced slightly but significantly, and SNP, SP-NO, and PGE(2) enhanced HO-1 protein induced by LPS/IFN-gamma. L-Arginine analogs N-nitro-L-arginine methyl ester (L-NAME) and N-nitro-L-arginine (NLA) significantly block HO-1 protein induced by LPS/IFN-gamma associated with a decrease in NO (not PGE(2)) production. And, NSAIDs aspirin and diclofenase dose dependently inhibited LPS/IFN-gamma-induced HO-1 protein accompanied by suppression of PGE(2) (not NO) production. PD98059 (a specific inhibitor of MEKK), but not SB203580 (a specific inhibitor of p38 kinase), attenuated PGE(2) (not SP-NO) induced HO-1 protein. Under UVC (100 J/m(2)) and UVB (50 J/m(2)) irradiation, PGE(2) or SP-NO treatment prevents cells from UVC or UVB-induced cell death, and HO-1 inhibitor tin protoporphyrin (SnPP) reverses the preventive effects of PGE(2) and SP-NO. The protective activity induced by PGE(2) on UVC or UVB irradiation-induced cell death was blocked by MAPK inhibitor PD98059 (not SB203580). These results demonstrated that inflammatory molecules NO and PGE(2) were potent inducers of HO-1 gene, and protected cells from UV-irradiation-induced cell death through HO-1 induction.
炎症过程中血红素加氧酶（HO）-1在多种细胞类型中均有诱导表达，但炎症分子一氧化氮（NO）和前列腺素E2（PGE2）的作用仍未明确。在此我们发现，包括硝普钠（SNP）和精胺亚硝基铁（SP-NO）在内的NO供体以及PGE2能显著刺激RAW264.7巨噬细胞中HO-1的表达，分别与培养基中NO和PGE2的交替诱导相关。NO供体对环氧化酶2蛋白和PGE2的产生也有诱导作用。在脂多糖和干扰素-γ（LPS/IFN-γ）存在的情况下，HO-1蛋白有轻微但显著的诱导表达，SNP、SP-NO和PGE2可增强LPS/IFN-γ诱导的HO-1蛋白表达。L-精氨酸类似物N-硝基-L-精氨酸甲酯（L-NAME）和N-硝基-L-精氨酸（NLA）能显著阻断LPS/IFN-γ诱导的HO-1蛋白表达，同时伴随NO（而非PGE2）产生的减少。此外，非甾体抗炎药阿司匹林和双氯芬酸能剂量依赖性地抑制LPS/IFN-γ诱导的HO-1蛋白表达，同时伴随PGE2（而非NO）产生的抑制。PD98059（MEKK的特异性抑制剂）而非SB203580（p38激酶的特异性抑制剂）可减弱PGE2（而非SP-NO）诱导的HO-1蛋白表达。在紫外线C（UVC，100 J/m2）和紫外线B（UVB，50 J/m2）照射下，PGE2或SP-NO处理可防止细胞发生UVC或UVB诱导的细胞死亡，而HO-1抑制剂锡原卟啉（SnPP）可逆转PGE2和SP-NO的保护作用。PGE2对UVC或UVB照射诱导的细胞死亡的保护活性可被丝裂原活化蛋白激酶抑制剂PD98059（而非SB203580）阻断。这些结果表明，炎症分子NO和PGE2是HO-1基因的有效诱导剂，并且通过诱导HO-1表达保护细胞免受紫外线照射诱导的细胞死亡。
