Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of FcγR Phagocytosis by Prostaglandin E2 in Alveolar Macrophages1
Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of FcγR Phagocytosis by Prostaglandin E2 in Alveolar Macrophages1
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10 号染色体上磷酸酶和张力蛋白同源物的激活介导肺泡巨噬细胞中前列腺素 E2 对 FcγR 吞噬作用的抑制1
作者：
C. Canetti;C. H. Serezani;Rachelle G Atrasz;E. White;D. Aronoff;M. Peters
PGE 2对巨噬细胞的吞噬和杀伤等防御功能具有重要的抑制作用，但其分子机制尚不清楚。PGE 2导致肺泡巨噬细胞（AM）中cAMP升高，进而激活cAMP效应靶点、蛋白激酶A和cAMP（Epac）-1激活的交换蛋白。我们现在报告Fcγ R诱导的PI 3 K/Akt和ERK-1/2激活在AM中被PGE 2抑制。通过特异性抑制AM中10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN），我们减弱了PGE 2和特异性Epac-1激动剂（8-pCPT-2′-O-Me-cAMP）对Fcγ R介导的吞噬作用和Akt/ERK-1/2激活的抑制作用; PTEN抑制也降低了PGE 2诱导的AM对细菌杀伤的抑制作用。此外，PGE 2和Epac-1激动剂诱导PTEN脂质磷酸酶活性的增加，这与PTEN上酪氨酸磷酸化的降低有关-这是已知调节PTEN活性的机制。使用药理学方法，我们证明了含Src同源性2的蛋白酪氨酸磷酸酶-1在PGE 2诱导的PTEN酪氨酸去磷酸化中的作用。总的来说，这些数据表明，PGE 2，通过Epac-1激活，增强SHP-1活性，导致增加的PTEN活性。我们认为这种机制有助于PGE 2抑制原代巨噬细胞中PI 3 K依赖性先天免疫信号传导的能力。
PGE2 has important inhibitory effects on the macrophage host defense functions of phagocytosis and killing, yet the molecular mechanisms involved remain to be fully elucidated. PGE2 causes an elevation of cAMP in alveolar macrophages (AMs), which in turn activates the cAMP effector targets, protein kinase A and the exchange protein activated by cAMP (Epac)-1. We now report that FcγR-induced PI3K/Akt and ERK-1/2 activation are inhibited by PGE2 in AMs. By specifically inhibiting the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in AMs, we attenuated the inhibitory effects of both PGE2 and a specific Epac-1 agonist (8-pCPT-2′-O-Me-cAMP) on FcγR-mediated phagocytosis and Akt/ERK-1/2 activation; PTEN inhibition also decreased PGE2-induced suppression of bacterial killing by AMs. Moreover, PGE2 and the Epac-1 agonist induced an increase in PTEN lipid phosphatase activity, and this was associated with decreased tyrosine phosphorylation on PTEN—a mechanism known to regulate PTEN activity. Using a pharmacological approach, we demonstrated a role for Src homology 2-containing protein tyrosine phosphatase-1 in the PGE2-induced tyrosine dephosphorylation of PTEN. Collectively, these data reveal that PGE2, via Epac-1 activation, enhances SHP-1 activity, resulting in increased PTEN activity. We suggest that this mechanism contributes to the ability of PGE2 to inhibit PI3K-dependent innate immune signaling in primary macrophages.
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前列腺素 E2 通过非磷脂酶 A2 机制限制花生四烯酸的利用率并抑制大鼠肺泡巨噬细胞中白三烯 B4 的合成。
DOI：
--
发表时间：
1993
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Christman,BW;Christman,JW;Dworski,R;Blair,IA;Prakash,C
通讯作者：
Prakash,C
DOI：
10.1165/rcmb.2004-0126oc
发表时间：
2005-02
影响因子：
6.4
作者：
E. White;Rachelle G Atrasz;E. G. Dickie;D. Aronoff;V. Stambolic;T. Mak;B. Moore;M. Peters-Golden
通讯作者：
E. White;Rachelle G Atrasz;E. G. Dickie;D. Aronoff;V. Stambolic;T. Mak;B. Moore;M. Peters-Golden
影响因子：
15.9
作者：
Tilley, SL;Coffman, TM;Koller, BH
通讯作者：
Koller, BH
DOI：
10.1073/pnas.96.18.10182
发表时间：
1999-08-31
影响因子：
11.1
作者：
Georgescu, MM;Kirsch, KH;Hanafusa, H
通讯作者：
Hanafusa, H
DOI：
10.1164/rccm.200301-041oc
发表时间：
2003-08-15
影响因子：
24.7
作者：
White, ES;Thannickal, VJ;Arenberg, DA
通讯作者：
Arenberg, DA