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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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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Endotoxins
Transcription Factors
Chemical activation
Inflammation
Sirolimus
Endotoxemia
Macrophages
Capillary Permeability
Infiltration
Caspase 3
DNA Damage
Shock
Apoptosis
Mortality
DNA

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, 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
Lee, Dong Keon ; Kim, Ji Hee ; Kim, Joohwan ; Choi, Seunghwan ; Park, Min Sik ; Park, Wonjin ; Kim, Suji ; Lee, Kyu Sun ; Kim, Taesam ; Jung, Jiwon ; Choi, Yoon Kyung ; Ha, Kwon Soo ; Won, Moo Ho ; Billiar, Timothy R. ; Kwon, Young Guen ; Kim, Young Myeong. / REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation. In: FASEB Journal. 2018 ; Vol. 32, No. 8. pp. 4585-4599.
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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.",
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Lee, DK, Kim, JH, Kim, J, Choi, S, Park, MS, Park, W, Kim, S, Lee, KS, Kim, T, Jung, J, Choi, YK, Ha, KS, Won, MH, Billiar, TR, Kwon, YG & Kim, YM 2018, 'REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation', FASEB Journal, vol. 32, no. 8, pp. 4585-4599. https://doi.org/10.1096/fj.201701436R

REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation. / Lee, Dong Keon; Kim, Ji Hee; Kim, Joohwan; Choi, Seunghwan; Park, Min Sik; Park, Wonjin; Kim, Suji; Lee, Kyu Sun; Kim, Taesam; Jung, Jiwon; Choi, Yoon Kyung; Ha, Kwon Soo; Won, Moo Ho; Billiar, Timothy R.; Kwon, Young Guen; Kim, Young Myeong.

In: FASEB Journal, Vol. 32, No. 8, 08.2018, p. 4585-4599.

Research output: Contribution to journalArticle

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T1 - REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation

AU - Lee, Dong Keon

AU - Kim, Ji Hee

AU - Kim, Joohwan

AU - Choi, Seunghwan

AU - Park, Min Sik

AU - Park, Wonjin

AU - Kim, Suji

AU - Lee, Kyu Sun

AU - Kim, Taesam

AU - Jung, Jiwon

AU - Choi, Yoon Kyung

AU - Ha, Kwon Soo

AU - Won, Moo Ho

AU - Billiar, Timothy R.

AU - Kwon, Young Guen

AU - Kim, Young Myeong

PY - 2018/8

Y1 - 2018/8

N2 - 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.

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-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.

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