Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 495, Issue 1, Pages 976-981Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2017.11.098
Keywords
Cereblon; Heme oxygenase-1; AMPK; HMGB1; CLP
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Funding
- National Research Foundation of Korea (NRF) [2015R1D1A1A02061508]
- Ministry of Education, Science and Technology [2015R1D1A1A02061508]
- National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea [1631040]
- Korea Health Promotion Institute [1631040] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2015R1D1A1A02061508] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Cereblon (CRBN) has a pleiotropic role in important cellular processes and is a potential therapeutic target in several diseases, including mental retardation, cancer, and metabolic disorders. The role of CRBN in polymicrobial sepsis induced by cecal ligation and puncture (CLP) was investigated using CRBN-deficient (KO) mice. Survival following CLP was significantly higher in KO mice compared to wild-type (WT) controls (50% vs 0% at day 6 after CLP). The improved survival of KO mice was accompanied by reduced peripheral blood bacterial load and lung injury. Serum tumor necrosis factor (TNF)-alpha and high mobility group box 1 (HMGB1) concentrations were significantly lower in KO mice than in WT mice. Peritoneal macrophages from KO mice with CLP-induced septic mouse had higher levels of activation of AMPK and heme oxygenase-1 (HO-1). Forced expression of CRBN in macrophage of KO mice suppressed activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and HO-1 and augmented expression of TNF-alpha, and HMGB1 as inhibition of AMPK by compound C. These studies demonstrate the contribution of CRBN expression to the pathogenesis of CLP-induced sepsis and peritoneal macrophage responses and suggest a novel therapeutic modality for polymicrobial sepsis. (C) 2017 Elsevier Inc. All rights reserved.
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