REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation

Dong Keon Lee, Ji Hee Kim, Joohwan Kim, Seunghwan Choi, Min Sik Park, Wonjin Park, Suji Kim, Kyu Sun Lee, Taesam Kim, Jiwon Jung, Yoon Kyung Choi, Kwon Soo Ha, Moo Ho Won, Timothy R. Billiar, Young Guen Kwon, Young Myeong Kim

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Abstract

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-kB (NF-kB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/2 macrophages. REDD-1 overexpression stimulated NF-kB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-kB activation was independent of 2 classic IKK-dependent NF-kB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IkBa, to elicit atypical NF-kB 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+/2 mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-kB activation by sequestering IkBa.

Original languageEnglish
Pages (from-to)4585-4599
Number of pages15
JournalFASEB Journal
Volume32
Issue number8
DOIs
Publication statusPublished - 2018 Aug

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Lee, D. K., Kim, J. H., Kim, J., Choi, S., Park, M. S., 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. (2018). REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation. FASEB Journal, 32(8), 4585-4599. https://doi.org/10.1096/fj.201701436R