PMID- 29547704 OWN - NLM STAT- MEDLINE DCOM- 20190211 LR - 20211204 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 32 IP - 8 DP - 2018 Aug TI - REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kappaB activation. PG - 4585-4599 LID - 10.1096/fj.201701436R [doi] AB - Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-kappaB (NF-kappaB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1(+/-) macrophages. REDD-1 overexpression stimulated NF-kappaB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-kappaB activation was independent of 2 classic IKK-dependent NF-kappaB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IkappaBalpha, to elicit atypical NF-kappaB activation during the delayed and persistent phases of inflammation after stimulation. Moreover, REDD-1 knockdown mitigated vascular inflammation and permeability in endotoxemic mice, resulting in decreases in immune cell infiltration, systemic inflammation, caspase-3 activation, apoptosis, and consequent mortality. We further confirmed the inflammatory and cytotoxic effects of REDD-1 in endotoxemic REDD-1(+/-) mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-kappaB activation by sequestering IkappaBalpha.-Lee, D.-K., Kim, J.-H., Kim, J., Choi, S., Park, M., Park, W., Kim, S., Lee, K.-S., Kim, T., Jung, J., Choi, Y. K., Ha, K.-S., Won, M.-H., Billiar, T. R., Kwon, Y.-G., Kim, Y.-M. REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kappaB activation. FAU - Lee, Dong-Keon AU - Lee DK AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Kim, Ji-Hee AU - Kim JH AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Kim, Joohwan AU - Kim J AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Choi, Seunghwan AU - Choi S AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Park, MinSik AU - Park M AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Park, Wonjin AU - Park W AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Kim, Suji AU - Kim S AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Lee, Kyu-Sun AU - Lee KS AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Kim, Taesam AU - Kim T AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Jung, Jiwon AU - Jung J AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Choi, Yoon Kyung AU - Choi YK AD - Department of Integrative Bioscience and Biotechnology, Konkuk University, Seoul, South Korea. FAU - Ha, Kwon-Soo AU - Ha KS AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Won, Moo-Ho AU - Won MH AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea. FAU - Billiar, Timothy R AU - Billiar TR AD - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. FAU - Kwon, Young-Guen AU - Kwon YG AD - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea. FAU - Kim, Young-Myeong AU - Kim YM AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180316 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Ddit4 protein, mouse) RN - 0 (Endotoxins) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Transcription Factors) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Caspase 3/metabolism MH - Cell Line MH - Endotoxemia/metabolism MH - Endotoxins/*metabolism MH - Gene Expression Regulation/drug effects MH - HEK293 Cells MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Inflammation/*chemically induced/*metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/metabolism MH - Mice MH - NF-KappaB Inhibitor alpha/metabolism MH - NF-kappa B/*metabolism MH - RAW 264.7 Cells MH - Signal Transduction/drug effects/physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Transcription Factors/*metabolism OTO - NOTNLM OT - IkappaBalpha OT - LPS OT - endotoxemia OT - macrophages OT - organ failure EDAT- 2018/03/17 06:00 MHDA- 2019/02/12 06:00 CRDT- 2018/03/17 06:00 PHST- 2018/03/17 06:00 [pubmed] PHST- 2019/02/12 06:00 [medline] PHST- 2018/03/17 06:00 [entrez] AID - 10.1096/fj.201701436R [doi] PST - ppublish SO - FASEB J. 2018 Aug;32(8):4585-4599. doi: 10.1096/fj.201701436R. Epub 2018 Mar 16.