Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor.
Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor.
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阿司匹林 (ASA) 和地塞米松 (DEX) 是广泛使用的抗炎药，但它们阻止炎症部位多形核中性粒细胞 (PMN) 积聚的机制仍不清楚。在此，我们报道了 ASA 和 DEX 对 PMN 浸润的抑制是阿司匹林触发的脂氧素 (ATL) 和糖皮质激素诱导的膜联蛋白 1 (ANXA1) 衍生肽共有的特性，这些肽均在体内产生并作用于脂氧素 A4 受体 (ALXR/FPRL1) 以阻止 PMN 渗出。这些结构多样的配体与重组人 ALXR 特异性直接相互作用，这一点通过特异性放射性配体结合和功能以及 PMN 受体的免疫沉淀来证明。此外，ATL 和 ANXA1 衍生肽的组合限制了 PMN 浸润并减少了体内炎症介质（即前列腺素和趋化因子）的产生。总之，这些结果表明内源性脂质和肽抗炎回路中在空间和时间上分离的功能冗余，其中 ATL 和特定的 ANXA1 衍生肽在 ALXR 上协同作用，下调 PMN 向炎症位点的募集。
Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A4 receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.
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DOI：
10.1073/pnas.95.24.14535
发表时间：
1998-11-24
影响因子：
11.1
作者：
Lim, LHK;Solito, E;Perretti, M
通讯作者：
Perretti, M
影响因子：
6
作者：
Cotter, MJ;Norman, KE;Ridger, VC
通讯作者：
Ridger, VC
影响因子：
2.9
作者：
Kang, Y;Taddeo, B;Fiore, S
通讯作者：
Fiore, S
影响因子：
64.8
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
15.3
作者：
Chiang, N;Fierro, I M;Gronert, K;Serhan, C N
通讯作者：
Serhan, C N