Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages
Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages
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DOI：
10.1074/jbc.m605146200
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发表时间：
2006-12-15
影响因子：
4.8
通讯作者：
Henson, Peter M.
中科院分区：
文献类型：
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作者：
Freire-de-Lima, Celio G.;Xiao, Yi Qun;Henson, Peter M.
凋亡细胞在释放促炎/促免疫原性细胞内内容物之前，被邻近组织细胞或巨噬细胞迅速吞噬。此外，凋亡细胞的识别是积极的抗炎和抗免疫原性的，产生抗炎介质，如转化生长因子- β (tgf - β)和抗炎二十烷类化合物。在这里，我们研究了tgf - β在抗炎类二十烷或过氧化物酶体增殖激活受体γ的协调表达中所起的作用，以及在抑制促炎脂质介质和一氧化氮（NO）中的作用。通过使用显性负TGF β II受体，TGF- β信号被阻断，并确定其参与凋亡细胞刺激的后果。tgf - β本身的诱导可能归因于凋亡细胞上暴露的磷脂酰丝氨酸，因此似乎驱动平衡的炎症介质反应。花生四烯酸释放、COX-2和前列腺素合成酶表达显著依赖于tgf - β的产生。另一方面，对tgf - β的需求也表现在对血栓烷合成酶和血栓烷，5-脂肪加氧酶和硫肽白三烯，以及诱导型一氧化氮合成酶和NO的抑制中。还发现了tgf - β依赖性精氨酸酶的诱导，这将进一步限制NO的产生。最后，凋亡细胞刺激了15-脂氧合酶和15-羟基二碳四烯酸的产生，这是一种通过过氧化物酶体增殖体激活受体- β和脂素a(4)产生的潜在抗炎途径，在该系统中也通过tgf - β依赖性途径上调。这些结果强烈表明，凋亡细胞对促炎介质产生的抑制是多效性的，并且显著依赖于tgf - β产生的刺激。
Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-gamma and in the suppression of pro-inflammatory lipid mediators and nitric oxide ( NO). By use of a dominant negative TGF beta II receptor, TGF-beta signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF-beta production. On the other hand, a requirement for TGF-beta was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF-beta-dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-beta, and lipoxin A(4) production, which were also up-regulated by a TGF-beta-dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production.