期刊
JOURNAL OF IMMUNOLOGY
卷 204, 期 10, 页码 2651-2660出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1901368
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资金
- March of Dimes Prematurity Research Centre-Ohio Collaborative
- American Academy of Pediatrics Marshall Klaus Award
- Society of Pediatric Research David G. Nathan Research Award
- Foundation for the National Institutes of Health [R21HD90856, R01HD 98389, U01 ES029234, R01AI123176, R01 AI113125]
- Burroughs Wellcome Fund
- Cincinnati Children's Hospital Medical Center Perinatal Infection and Inflammation Collaborative Grant
Preterm birth (PTB) is a major cause of neonatal mortality and morbidity, often triggered by chorioamnionitis or intrauterine inflammation (IUI) with or without infection. Recently, there has been a strong association of IL-1 with PTB. We hypothesized that IL-1R-associated kinase 1 (IRAK1), a key signaling mediator in the TLR/IL-1 pathway, plays a critical role in PTB. In human fetal membranes (FM) collected immediately after birth from women delivering preterm, p-IRAK1 was significantly increased in all the layers of FM with chorioamnionitis, compared with no-chorioamnionitis subjects. In a preterm rhesus macaque model of IUI given intra-amniotic LPS, induction of p-IRAK1 and downstream proinflammatory signaling mediators were seen in the FM. In a C57BL/6J wild-type PTB mouse model of IUI given intrauterine LPS, an IRAK1 inhibitor significantly decreased PTB and increased live birth in a dose-dependent manner. Furthermore, IRAK1 knockout mice were protected from LPS-induced PTB, which was seen in wild-type controls. Activation of IRAK1 was maintained by K63-mediated ubiquitination in preterm FM of humans with chorioamnionitis and rhesus and mouse IUI models. Mechanistically, IRAK1 induced PTB in the mouse model of IUI by upregulating expression of COX-2. Thus, our data from human, rhesus, and mouse demonstrates a critical role IRAK1 in IUI and inflammation-associated PTB and suggest it as potential therapeutic target in IUI-induced PTB.
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