Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia
Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia
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DOI：
10.1183/09031936.00089008
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发表时间：
2009-02-01
影响因子：
24.3
通讯作者：
Boulares, A. H.
中科院分区：
文献类型：
--
作者：
Naura, A. S.;Datta, R.;Boulares, A. H.
诱导型一氧化氮合酶（iNOS）的抑制作用，最近被证明对过敏原的挑战，在人类哮喘，引起严重关注的蛋白质在疾病中的作用。本研究采用卵清蛋白诱导的小鼠嗜酸性粒细胞增多症模型，从多聚腺苷二磷酸核糖聚合酶-1（PARP-1）和DNA氧化损伤的角度探讨了诱导型一氧化氮合酶（iNOS）在卵清蛋白诱导的嗜酸性粒细胞增多症中的作用。在过敏原激发后，iNOS表达是氧化性DNA损伤和PARP-1活化所必需的。PARP-1是NOS表达和蛋白质硝化所必需的，这种需要与核因子-κ B有关。PARP-1是卵清蛋白刺激后iNOS相关副产物的重要底物。PARP-1的硝化作用阻断了其聚ADP-核糖基化活性。在卵清蛋白暴露的PARP-1（-/-）小鼠中，白细胞介素-5的重建逆转了嗜酸性粒细胞增多和部分粘液产生，而没有逆转NOS表达，本研究结果表明，诱导型一氧化氮合酶和多聚腺苷酸之间存在相互关系。（ADP-核糖）聚合酶-1，并表明诱导型一氧化氮合酶的表达可能是嗜酸性粒细胞增多症后白细胞介素-5的生产。诱导型一氧化氮合酶可能是氧化性DNA损伤和粘液产生的全部表现所必需的。这种可免除性可能部分解释了所报道的诱导型一氧化氮合酶抑制剂在预防人类过敏原诱导的炎症中的无效性。
Inducible nitric oxide synthase (iNOS) inhibition was recently shown to exert no effect on allergen challenge in human asthma, raising serious concerns about the role of the protein in the disease. The present study investigated the role of iNOS in ovalbumin-induced eosinophilia from the perspective of its relationship with poly(ADP-ribose) polymerase-1 (PARP-1) and oxidative DNA damage.A mouse model of ovalbumin-induced eosinophilia was used to conduct the studies.iNOS-associated protein nitration and tissue damage were partially responsible for allergen-induced eosinophilia. iNOS expression was required for oxidative DNA damage and PARP-1 activation upon allergen challenge. PARP-1 was required for NOS expression and protein nitration, and this requirement was connected to nuclear factor-kappa B. PARP-1 was an important substrate for iNOS-associated by-products after ovalbumin-challenge. PARP-1 nitration blocked its poly(ADP-ribosyl)ation activity. Interleukin-5 re-establishment in ovalbumin-exposed PARP-1(-/-) mice reversed eosinophilia and partial mucus production without a reversal of NOS expression, concomitant protein nitration or associated DNA damage.The present results demonstrate a reciprocal relationship between inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 and suggest that expression of inducible nitric oxide synthase may be dispensable for eosinophilia after interleukin-5 production. Inducible nitric oxide synthase may be required for oxidative DNA damage and full manifestation of mucus production. Such dispensability may explain, in part, the reported ineffectiveness of inducible nitric oxide synthase inhibition in preventing allergen-induced inflammation in humans.