Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation
Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation
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DOI：
10.1172/jci11638
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Henson, PM
中科院分区：
文献类型：
--
作者：
Huynh, MLN;Fadok, VA;Henson, PM
巨噬细胞在体外摄取凋亡细胞诱导TGF-β 1分泌，导致抗炎作用和抑制促炎介质。在这里，我们在体内表明，直接滴注凋亡细胞增强了急性炎症的解决。这种增强似乎需要磷脂酰丝氨酸（PS）对凋亡细胞和TGF-β 1的局部诱导。使用巯基乙酸盐刺激的腹膜或LPS刺激的肺，我们检测了凋亡细胞摄取对TGF-β 1诱导的影响。活的或调理的凋亡的人Jurkat T细胞，或凋亡的PLB-985细胞，在凋亡过程中不表达PS的人单核细胞，未能诱导TGF-β 1。PS脂质体，或PS直接转移到PLB-985表面膜，恢复TGF-β 1诱导。将凋亡细胞滴入LPS刺激的肺中可降低支气管肺泡灌洗液（BALF）中的促炎趋化因子水平。此外，BALF中的总炎性细胞计数在凋亡细胞滴注后1-5天显著减少，这种作用可以通过调理或共滴注TGF-β 1中和抗体来逆转。这种减少是由于中性粒细胞的早期减少和淋巴细胞和巨噬细胞的后期减少。总之，凋亡细胞的识别和清除，通过暴露的PS和其受体的连接，诱导TGF-β 1分泌，导致炎症的加速解决。
Ingestion of apoptotic cells in vitro by macrophages induces TGF-beta1 secretion, resulting in an anti-inflammatory effect and suppression of proinflammatory mediators. Here, we show in vivo that direct instillation of apoptotic cells enhanced the resolution of acute inflammation. This enhancement appeared to require phosphatidylserine (PS) on the apoptotic cells and local induction of TGF-beta1. Working with thioglycollate-stimulated peritonea or LPS-stimulated lungs, we examined the effect of apoptotic cell uptake on TGF-beta1 induction. Viable or opsonized apoptotic human Jurkat T cells, or apoptotic PLB-985 cells, human monomyelocytes that do not express PS during apoptosis, failed to induce TGF-beta1. PS liposomes, or PS directly transferred onto the PLB-985 surface membranes, restored the TGF-beta1 induction. Apoptotic cell instillation into LPS-stimulated lungs reduced proinflammatory chemokine levels in the bronchoalveolar lavage fluid (BALF). Additionally, total inflammatory cell counts in the BALF were markedly reduced 1-5 days after apoptotic cell instillation, an effect that could be reversed by opsonization or coinstillation of TGF-beta1 neutralizing antibody. This reduction resulted from early decrease in neutrophils and later decreases in lymphocytes and macrophages. In conclusion, apoptotic cell recognition and clearance, via exposure of PS and ligation of its receptor, induce TGF-beta1 secretion, resulting in accelerated resolution of inflammation.