A role for IL-1 receptor-associated kinase-M in prostaglandin E2-induced immunosuppression post-bone marrow transplantation.
A role for IL-1 receptor-associated kinase-M in prostaglandin E2-induced immunosuppression post-bone marrow transplantation.
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DOI：
10.4049/jimmunol.0902828
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Moore BB
中科院分区：
文献类型：
--
作者：
Hubbard LL;Ballinger MN;Thomas PE;Wilke CA;Standiford TJ;Kobayashi KS;Flavell RA;Moore BB
在免疫重建后，造血干细胞移植患者通常表现出免疫功能下降，特别容易受到肺部感染。在同基因骨髓移植（BMT）的小鼠模型中，我们以前报道过PGE 2在BMT小鼠的肺中过量产生，显著损害宿主对铜绿假单胞菌的防御。BMT后宿主防御的这种损害也以肺泡巨噬细胞（AM）吞噬作用减少、细菌杀伤和TNF-α和半胱氨酰白三烯产生减少为标志。然而，PGE 2的过度产生抑制BMT后肺宿主防御的机制尚不清楚。由于IL-1 R相关激酶（IRAK）-M是MyD 88依赖性IL-1 R/TLR信号传导和巨噬细胞功能的已知抑制剂，我们试图确定IRAK-M是否参与BMT后PGE 2诱导的免疫抑制。我们发现，IRAK-M的表达升高3.5倍，在骨髓移植AM相对于对照AM，这是与AM的PGE 2的过度生产。此外，BMT小鼠骨髓中IRAK-M的基因消除恢复了宿主对铜绿假单胞菌的防御。尽管AM过度产生PGE 2和E前列腺素2受体表达升高，但在BMT后不存在IRAK-M的情况下，AM吞噬作用、杀伤作用以及半胱氨酰白三烯和TNF-α的产生得到恢复。此外，在不存在IRAK-M的情况下，用PGE 2处理不抑制AM吞噬作用。这些数据表明，IRAK-M在骨髓移植后造血区室中的缺乏增强了肺宿主防御，并减轻了AM对PGE 2抑制作用的敏感性。因此，限制BMT后IRAK-M升高的策略可能有效降低患者对感染的易感性。
Following immune reconstitution, hematopoietic stem cell transplant patients often display reduced immune function and are especially susceptible to lung infections. In a mouse model of syngeneic bone marrow transplantation (BMT), we previously reported that PGE2 is overproduced in lungs of BMT mice, significantly impairing host defense against Pseudomonas aeruginosa. This impairment in host defense post-BMT is also marked by diminished alveolar macrophage (AM) phagocytosis, bacterial killing, and production of TNF-α and cysteinyl leukotrienes. However, a mechanism by which overproduction of PGE2 suppresses pulmonary host defense post-BMT is unknown. As IL-1R–associated kinase (IRAK)-M is a known inhibitor of MyD88-dependent IL-1R/TLR signaling and macrophage function, we sought to determine whether IRAK-M is involved in PGE2-induced immunosuppression post-BMT. We found that IRAK-M expression is elevated 3.5-fold in BMT AMs relative to control AMs, and this is related to AM overproduction of PGE2. Furthermore, genetic ablation of IRAK-M in the bone marrow of BMT mice restores host defense against P. aeruginosa. Despite AM overproduction of PGE2 and elevated E prostanoid 2 receptor expression, AM phagocytosis, killing, and production of cysteinyl leukotrienes and TNF-α are restored in the absence of IRAK-M post-BMT. Also, treatment with PGE2 does not inhibit AM phagocytosis in the absence of IRAK-M. These data suggest that the absence of IRAK-M in the hematopoietic compartment post-BMT enhances pulmonary host defense and mitigates AM sensitivity to the inhibitory effects of PGE2. Therefore, strategies to limit IRAK-M elevation post-BMT may be efficacious in reducing patient susceptibility to infection.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
15.3
作者：
Palecanda, A;Paulauskis, J;Al-Mutairi, E;Imrich, A;Qin, G;Suzuki, H;Kodama, T;Tryggvason, K;Koziel, H;Kobzik, L
通讯作者：
Kobzik, L
DOI：
10.1084/jem.20031237
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Doyle SE;O'Connell RM;Miranda GA;Vaidya SA;Chow EK;Liu PT;Suzuki S;Suzuki N;Modlin RL;Yeh WC;Lane TF;Cheng G
通讯作者：
Cheng G
影响因子：
3.1
作者：
Kooguchi, K;Hashimoto, S;Sawa, T
通讯作者：
Sawa, T
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG